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Simple Summary: Immunity combined with ferroptosis is being considered as a new tumor treatment modality, and its regulation in head and neck squamous cell carcinoma is still unknown. The purpose of this study was to look into the potential molecular biological roles of immune ferroptosis genes in head and neck squamous cell carcinoma. The 12-IFRM signatures were successfully constructed and classified into high- and low-risk groups using the TCGA database and related data resources. In patients with head and neck squamous cell carcinoma, feature-based risk scores were more predictive of survival than traditional clinicopathological features. Furthermore, the expression of CD8+T cells and macrophage M0 differed significantly between the two groups. The expression of TNFSF9 and CD44 in the high-risk groups was significantly increased compared with the low-risk groups. Next, we found a higher proportion of high-risk mutations than in the low-risk group. In addition, the high-risk group was more sensitive to some chemotherapy drugs. Finally, we performed correlation analysis on the model genes. In this paper, the 12-IFRM signatures was developed with promising application prospects for predicting the clinical outcomes and treatment outcomes in head and neck squamous cell carcinoma. Ferroptosis is a new type of programmed cell death that plays a pivotal role in a variety of tumors. Moreover, immunity is closely related to ferroptosis. However, immune-ferroptosis-related mRNAs (IFRMs) are still not fully understood in the regulation of head and neck squamous cell carcinoma (HNSC). The purpose of this paper was to investigate the IFRMs prediction of HNSC and its possible molecular biological role. RNA-Seq and related clinical data were mined from the TCGA database, ImmPort database, GeneCards database, FerrDb database, and previous data. In R software, the "DESeq2" package was used to analyze the differential expression of IFRMs. We used univariate Cox analysis to judge the prognosis of the IFRMs. Using the least absolute shrinkage and selection operator (LASSO) and Cox regression, a prediction model for 12 IFRMs was established. In this study, the Kaplan–Meier survival curve and receiver operating characteristic (ROC) curve analysis were used to evaluate the prediction results. Moreover, factors such as immune landscape, somatic mutations, and drug susceptibility are also discussed. We successfully constructed the signature of 12-IFRMs. The two risk groups were classified according to the risk score obtained by this signature. Compared with conventional clinicopathological features, the characteristic-based risk score was more predictive of survival in patients with HNSC. Furthermore, the expression of CD8+T cells and macrophage M0 differed significantly between the two groups. Moreover, the expression of TNFSF9 and CD44 in high-risk groups was significantly increased compared with the low-risk groups. Then, we found a higher proportion of high-risk mutations than in the low-risk group. Next, the high-risk group was more sensitive to chemotherapy drugs such as bosutinib, docetaxel, erlotinib, gefitinib, imatinib, lapatinib, and sorafenib. Finally, an in-depth analysis of the association and potential value of the 12 genes was performed. In summary, the 12-IFRM signatures established in this paper had good application prospects and could be effectively used to predict the clinical outcome and treatment response of head and neck squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper presents an extended version of the Cox regression model to examine heterogeneous effects of risk factors on disease subtypes defined by a continuous biomarker. This approach can be easily applied to cancer studies and is accessible to researchers via user-friendly R scripts. Molecular pathologic diagnosis is important in clinical (oncology) practice. Integration of molecular pathology into epidemiological methods (i.e., molecular pathological epidemiology) allows for investigating the distinct etiology of disease subtypes based on biomarker analyses, thereby contributing to precision medicine and prevention. However, existing approaches for investigating etiological heterogeneity deal with categorical subtypes. We aimed to fully leverage continuous measures available in most biomarker readouts (gene/protein expression levels, signaling pathway activation, immune cell counts, microbiome/microbial abundance in tumor microenvironment, etc.). We present a cause-specific Cox proportional hazards regression model for evaluating how the exposure–disease subtype association changes across continuous subtyping biomarker levels. Utilizing two longitudinal observational prospective cohort studies, we investigated how the association of alcohol intake (a risk factor) with colorectal cancer incidence differed across the continuous values of tumor epigenetic DNA methylation at long interspersed nucleotide element-1 (LINE-1). The heterogeneous alcohol effect was modeled using different functions of the LINE-1 marker to demonstrate the method's flexibility. This real-world proof-of-principle computational application demonstrates how the new method enables visualizing the trend of the exposure effect over continuous marker levels. The utilization of continuous biomarker data without categorization for investigating etiological heterogeneity can advance our understanding of biological and pathogenic mechanisms. [ABSTRACT FROM AUTHOR]

Surgery has contributed to unveil a tumor behavior that is difficult to reconcile with the models of tumorigenesis based on gradualism. The postsurgical patterns of progression include unexpected features such as distant interactions and variable rhythms. The underlying evidence can be summarized as follows: (1) the resection of the primary tumor is able to accelerate the evolution of micrometastasis in early stages, and (2) the outcome is transiently opposed in advanced tumors. The objective of this paper is to give some insight into tumorigenesis and surgery-related effects, by applying the concepts of the evolutionary theory in those tumor behaviors that gompertzian and tissular-centered models are unable to explain. According to this view, tumors are the consequence of natural selection operating at the somatic level, which is the basic mechanism of tumorigenesis, notwithstanding the complementary role of the intrinsic constrictions of complex networks. A tumor is a complicated phenomenon that entails growth, evolution and development simultaneously. So, an evo-devo perspective can explain how and why tumor subclones are able to translate competition from a metabolic level into neoangiogenesis and the immune response. The paper proposes that distant interactions are an extension of the ecological events at the local level. This notion explains the evolutionary basis for tumor dormancy, and warns against the teleological view of tumorigenesis as a process directed towards the maximization of a concrete trait such as aggressiveness. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new type of programmed cell death that plays a pivotal role in a variety of tumors. Moreover, immunity is closely related to ferroptosis. However, immune-ferroptosis-related mRNAs (IFRMs) are still not fully understood in the regulation of head and neck squamous cell carcinoma (HNSC). The purpose of this paper was to investigate the IFRMs prediction of HNSC and its possible molecular biological role. RNA-Seq and related clinical data were mined from the TCGA database, ImmPort database, GeneCards database, FerrDb database, and previous data. In R software, the “DESeq2” package was used to analyze the differential expression of IFRMs. We used univariate Cox analysis to judge the prognosis of the IFRMs. Using the least absolute shrinkage and selection operator (LASSO) and Cox regression, a prediction model for 12 IFRMs was established. In this study, the Kaplan–Meier survival curve and receiver operating characteristic (ROC) curve analysis were used to evaluate the prediction results. Moreover, factors such as immune landscape, somatic mutations, and drug susceptibility are also discussed. We successfully constructed the signature of 12-IFRMs. The two risk groups were classified according to the risk score obtained by this signature. Compared with conventional clinicopathological features, the characteristic-based risk score was more predictive of survival in patients with HNSC. Furthermore, the expression of CD8+T cells and macrophage M0 differed significantly between the two groups. Moreover, the expression of TNFSF9 and CD44 in high-risk groups was significantly increased compared with the low-risk groups. Then, we found a higher proportion of high-risk mutations than in the low-risk group. Next, the high-risk group was more sensitive to chemotherapy drugs such as bosutinib, docetaxel, erlotinib, gefitinib, imatinib, lapatinib, and sorafenib. Finally, an in-depth analysis of the association and potential value of the 12 genes was performed. In summary, the 12-IFRM signatures established in this paper had good application prospects and could be effectively used to predict the clinical outcome and treatment response of head and neck squamous cell carcinoma.

Cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited response to a target antigen. The growing interest over the past two decades in harnessing the immune system to eradicate cancer has been accompanied by heightened efforts to characterize cytokines and exploit their vast signaling networks to develop cancer treatments. The goal of this paper is to review the major cytokines involved in cancer immunotherapy and discuss their basic biology and clinical applications. The paper will also describe new cytokines in pre-clinical development, combinations of biological agents, novel delivery mechanisms, and potential directions for future investigation using cytokines. [ABSTRACT FROM AUTHOR]

Therapeutic cancer vaccines have the potential to generate a long lasting immune response that will destroy tumor cells with specificity and safety, in contrast to many other current cancer therapies. Clinical success to date has been limited by a number of factors including choice of immunogenic cancer rejection antigens, optimization of vaccine platforms and immune adjuvants to effectively polarize the immune response, and incorporation of strategies to reverse cancer mediated immune suppression by utilization of effective adjuvant/immune modulators. WT-1 (Wilms' tumor gene 1) is a cancer antigen that is required for tumorigenesis, expressed in a high percentage of tumor cells and rarely expressed in adult normal cells. Moreover spontaneous immunity to WT-1 is seen in cancer patients and can be augmented with various therapeutic vaccine approaches. IRX-2 is an immune modulator with demonstrated preclinical and clinical pleiotropic immune activities including enhancement of the immune response to potential tumor antigens. This paper presents the rationale and preclinical data for utilizing the WT-1 tumor antigen in a novel vaccine platform consisting of a synthetic long peptide containing multiple class I and class II epitopes in combination with the IRX-2 immunomodulatory regimen to overcome immuno-suppressive pathways and enhance the anti-tumor response. [ABSTRACT FROM AUTHOR]

Simple Summary: Oncolytic viruses are emerging immunotherapeutics in cancer treatments. The conflicting role of innate immunity in the antitumor activity of oncolytic viruses is still a matter of debate. The STING-dependent DNA sensing axis is considered detrimental for viral replication and cancer cell clearance. Accordingly, we observed that STING loss in tumor cells was associated with improved lytic potential by a herpes-based oncolytic virus. However, STING-knockout cancer cells infected with the oncolytic virus showed impaired immunogenicity, as immunogenic cell death was improperly triggered. In agreement with these observations, STING-knockout tumors raised in a murine syngeneic model were more resistant to a combined treatment of the oncolytic virus with PD-1 blockade. The present study demonstrates the antitumor benefit of antiviral immunity and sheds lights on the mechanisms of immune resistance to oncovirotherapy exerted by STING-loss in tumor cells. The dichotomic contribution of cancer cell lysis and tumor immunogenicity is considered essential for effective oncovirotherapy, suggesting that the innate antiviral immune response is a hurdle for efficacy of oncolytic viruses. However, emerging evidence is resizing this view. By sensing cytosolic DNA, the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) axis can both counteract viral spread and contribute to the elicitation of adaptive immunity via type I interferon responses. In this paper, we analyzed the tumor-resident function of Sting-mediated DNA sensing in a combined approach of oncovirotherapy and PD-1 immune checkpoint blockade, in an immunocompetent murine model. While supporting increased lytic potential by oncolytic HER2-retargeted HSV-1 in vitro and in vivo, Sting-knockout tumors showed molecular signatures of an immunosuppressive tumor microenvironment. These signatures were correspondingly associated with ineffectiveness of the combination therapy in a model of established tumors. Results suggest that the impairment in antiviral response of Sting-knockout tumors, while favoring viral replication, is not able to elicit an adequate immunotherapeutic effect, due to lack of immunogenic cell death and the inability of Sting-knockout cancer cells to promote anti-tumor adaptive immune responses. Accordingly, we propose that antiviral, tumor-resident Sting provides fundamental contributions to immunotherapeutic efficacy of oncolytic viruses. [ABSTRACT FROM AUTHOR]

Simple Summary: Mitochondria in cancer cells produce reactive oxygen species, inducing a vicious cycle between oxidative stress, genomic instability, and cancer development. However, too high oxidative stress kills tumor cells. Cancer cells protect themselves directly by increasing antioxidant expression. In addition, shifting the phenotype of immune cells from ant-oncogenic to pro-oncogenic reduces reactive oxygen levels within the tumor microenvironment to maintain tumor growth. This review shows how noncoding RNAs may regulate mitochondrial function, antioxidant expression, and immune cell reprogramming. Interestingly, noncoding RNAs in microvesicles secreted by mesenchymal stem cells, cancer-associated fibroblasts, and cancer cells contribute to this immune cell reprogramming. Further research on the role of noncoding RNAs in the communication between cell types in the tumor microenvironment is warranted. Mitochondria in cancer cells tend to overproduce reactive oxygen species (ROS), inducing a vicious cycle between mitochondria, ROS, genomic instability, and cancer development. The first part of this review deals with the role of noncoding RNAs in regulating mitochondrial ROS production and the expression of antioxidants in cancer cells, preventing the increase of ROS in the tumor microenvironment. In addition, cytotoxic T and natural killer cells release high levels of ROS, inducing cell death, while anti-immune regulatory T cells, tumor-associated M2 macrophages, and myeloid-derived suppressor cells, at least at the initial stage of tumor growth, release low levels of ROS supporting tumor growth. Therefore, this review's second part deals with noncoding RNAs' role in regulating the metabolic reprogramming of immune cells about ROS release. Furthermore, the enrichment of noncoding RNAs in microvesicles allows communication between cell types in a tumor and between a tumor and tumor-adjacent tissues. Therefore, the third part illustrates how noncoding RNA-containing microvesicles secreted by mesenchymal stem cells and primary tumor cells may primarily aid the shift of immune cells to a pro-oncogenic phenotype. Conversely, microvesicles released by tumor-adjacent tissues may have the opposite effect. Our review reveals that a specific noncoding RNA may affect oxidative stress by several mechanisms, which may have opposite effects on tumor growth. Furthermore, they may be involved in mechanisms other than regulating oxidative stress, which may level out their effects on oxidative stress and tumor growth. In addition, several noncoding RNAs might share a specific function, making it very unlikely that intervening with only one of these noncoding RNAs will block this particular mechanism. Overall, further validation of the interaction between noncoding RNAs about cancer types and stages of tumor development is warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of immune checkpoint inhibitors (ICI) is expanding with the approval for locally advanced and metastasizing keratinocyte carcinoma. Most cases, however, are non-aggressive. Systemic therapy remains limited by severe side effects. Local administration could broaden ICI, but an adequate immune response might require an immune-attractive adjuvant such as ablative fractional laser (AFL). Accordingly, aiming to broaden the field of ICI to keratinocyte carcinoma, this study investigates the intratumoral injection of anti-PD1 with and without AFL in basal cell carcinoma (BCC), exploring anti-PD1 concentration, immune cell infiltration, tumor response, and safety. With the results of the study showing the feasibility of intratumoral anti-PD1 and increase in immune cell infiltration and tumor reduction upon combined anti-PD1 and AFL, local, hence broader, application of anti-PD1 holds potential for future treatment of non-aggressive keratinocyte carcinomas. The use of immune checkpoint inhibitors (ICI) is expanding with the approval for advanced/metastatic keratinocyte carcinoma; however, most tumors are non-aggressive. Local administration could broaden ICI, but adequate immune response might require an immune-attractive adjuvant such as ablative fractional laser (AFL). Accordingly, this study aimed to explore intratumoral injection of anti-PD1 with and without AFL in basal cell carcinoma (BCC), exploring anti-PD1 concentration, immune cell infiltration, tumor response, and safety. This open-label, proof-of-concept trial investigated intratumoral anti-PD1 + AFL combination therapy versus anti-PD1 or AFL monotherapy in 28 BCC patients. The primary endpoints were immune cell infiltration evaluated immunohistochemically and clinical tumor response after 3 months. The secondary outcomes were tumoral drug concentration and safety. The most robust response was obtained following intervention with combined anti-PD1+AFL, leading to a ~2.5-fold increase in CD3+ cells (p = 0.027), and tumor reduction ≥25% in 73%, including two tumors with complete remission. Upon anti-PD1 monotherapy, a slight decrease in CD3+ cells was observed while a non-significant increase following AFL was seen. Tumor reduction ≥25% was seen in 45% and 50%, respectively, after anti-PD1 and AFL monotherapy. The CD8/CD3 ratio remained unchanged after anti-PD1+AFL and anti-PD1 monotherapy, while AFL led to a decreased ratio. A non-significant decline in the Foxp3/CD3 ratio was observed for all groups. Side-effects were mild with no systemic drug concentration detected. Intratumoral anti-PD1 injection is feasible, and a single exposure to locally injected anti-PD1 with adjuvant AFL increased immune cell infiltration and reduction in BCC with limited side-effects. [ABSTRACT FROM AUTHOR]

Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available immunotherapies. It is therefore of paramount importance to identify the prognostic and predictive factors of tumor response/resistance and to design effective therapeutic strategies to overcome primary resistance and improve the efficacy of immunotherapy. The aim of this review is to underline the influence of the tumor and host metabolism on the antitumor immune response and to discuss possible strategies to improve the efficacy of available treatments by targeting the specific metabolic pathways in tumors or immune cells and by modifying patients' nutritional statuses. A systematic search of the Medline and EMBASE databases was carried out to identify scientific papers published until February 2020, which reported original research articles on the influence of tumor or host metabolism on antitumor immune response. The literature data showed the key role of glycolysis and mitochondrial oxidative phosphorylation, arginine, tryptophan, glutamine, lipid metabolism and microbiome on immune cell function. Moreover, specific nutritional behaviors, such as a low dietary intake of vitamin C, low glycemic index and alpha-linolenic acid, eicosapentenoic acid, docosahexaenoic acid, ornithine ketoglutarate, tryptophan and probiotic supplementation were associated with the potential clinical benefits from the currently available immunotherapies. [ABSTRACT FROM AUTHOR]

Simple Summary: The commensal microbiome in the human body must always be considered as a potential factor in carcinogenesis that may play a crucial role in the occurrence and progression of lung cancer. Herein, we give great details about the biological processes involved in lung cancer mediated by the microbiome. Potential mechanisms include regulating host immune activity by means of a variety of pathogenic factors, dysregulating host metabolism as a result of microbiome alterations, and microbiome dysbiosis, which are well elucidated in this article. The human commensal microbiome existing in an internal environment is relatively consistent with that of the host. The presence of bacterial dysbiosis, on the other hand, promptly results in the termination of this symbiotic association. The altered microbial structure in the lung may be responsible for the development of lung cancer by controlling the host's inflammatory response and influencing a variety of immunological pathways. More and more studies have pointed to the fact that the commensal microbiota plays a vital role in both the development of tumors and the body's response to lung cancer treatment. Microbiome dysbiosis, genotoxicity, virulence effect, and epigenetic dysregulations are some of the potential mechanisms that may lie behind the process of tumorigenesis that is mediated by microbiome. Other potential mechanisms include regulating host immune activity through a variety of pathogenic factors, dysregulating host metabolism as a result of microbiome alterations, and microbiome dysbiosis. In this historical overview, we go through some of the more recent mechanistic discoveries into the biological processes that are involved in lung cancer that are caused by bacteria. Without a question, obtaining a greater knowledge of the dynamic link between the lung microbiome and lung cancer has the potential to inspire the development of innovative early detection and customized treatment methods for lung cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: This review focuses on eRNAs and the several mechanisms by which they can regulate gene expression. In particular we describe here the most recent examples of eRNAs dysregulated in cancer or involved in the immune escape of tumor cells. Enhancer RNAs (eRNAs) are non-coding RNAs (ncRNAs) transcribed in enhancer regions. They play an important role in transcriptional regulation, mainly during cellular differentiation. eRNAs are tightly tissue- and cell-type specific and are induced by specific stimuli, activating promoters of target genes in turn. eRNAs usually have a very short half-life but in some cases, once activated, they can be stably expressed and acquire additional functions. Due to their critical role, eRNAs are often dysregulated in cancer and growing number of interactions with chromatin modifiers, transcription factors, and splicing machinery have been described. Enhancer activation and eRNA transcription have particular relevance also in inflammatory response, placing the eRNAs at the interplay between cancer and immune cells. Here, we summarize all the possible molecular mechanisms recently reported in association with eRNAs activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammasomes play a key role in mediating innate immunity by regulating the processing and production of pro-inflammatory cytokines and eliminating foreign pathogens via pyroptosis. The expression of Epstein–Barr virus (EBV) viral antigens during EBV infection, a known causative agent of nasopharyngeal carcinoma (NPC), can trigger host's antiviral immune response through activation of the inflammasomes and subsequent production of pro-inflammatory cytokines. This review explores the roles of inflammasomes during viral infection, the possible impact of inflammasomes on oncogenesis in EBV-associated NPC, and current developments in targeting inflammasomes for cancer treatment. With the contrasting roles of inflammasomes reported in different types of cancers, this paper aims to inspire further investigations into the exact role and mechanism of inflammasomes in EBV-associated NPC, as well as the therapeutic potentials of targeting inflammasomes in NPC. Epstein–Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host's antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC. [ABSTRACT FROM AUTHOR]

Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available immunotherapies. It is therefore of paramount importance to identify the prognostic and predictive factors of tumor response/resistance and to design effective therapeutic strategies to overcome primary resistance and improve the efficacy of immunotherapy. The aim of this review is to underline the influence of the tumor and host metabolism on the antitumor immune response and to discuss possible strategies to improve the efficacy of available treatments by targeting the specific metabolic pathways in tumors or immune cells and by modifying patients’ nutritional statuses. A systematic search of the Medline and EMBASE databases was carried out to identify scientific papers published until February 2020, which reported original research articles on the influence of tumor or host metabolism on antitumor immune response. The literature data showed the key role of glycolysis and mitochondrial oxidative phosphorylation, arginine, tryptophan, glutamine, lipid metabolism and microbiome on immune cell function. Moreover, specific nutritional behaviors, such as a low dietary intake of vitamin C, low glycemic index and alpha-linolenic acid, eicosapentenoic acid, docosahexaenoic acid, ornithine ketoglutarate, tryptophan and probiotic supplementation were associated with the potential clinical benefits from the currently available immunotherapies.

Simple Summary: T/NK-cell non-Hodgkin lymphomas (NHLs) represent approximately 10% of all NHLs and most patients have a poor outcome using current treatment options. Molecules involved in the host response against lymphoma cells are currently being investigated in an effort to develop novel therapeutic strategies combining targeted therapy and immunotherapy. In this study, we show that expression of STING, a key protein in the cGAS–STING immune response pathway, is restricted to lymphomas of T- and NK-cell origin and seems to be down regulated in B-cell NHLs. These results are based on the analysis of 14 lymphoma cell lines of various types at the RNA and protein level and immunohistochemical analysis of a large number of B-cell (n = 265) and T/NK-cell (n = 158) NHLs obtained from previously untreated patients from three institutions. In these patient cohorts, STING is differentially expressed among T/NK-cell NHLs, whereas all B-cell NHLs were negative for STING expression. Thus, STING represents a novel biomarker and therapeutic target in T- and NK-cell lymphomas with direct immunotherapeutic implications, since modulators of cGAS–STING activity are already available for clinical use, and could therefore be used to benefit patients with these difficult-to-treat diseases. The expression patterns of stimulator of interferon genes (STING) were investigated in a cohort of 158 T- and natural killer (NK)-cell and 265 B-cell non-Hodgkin lymphomas (NHLs), as well as in control reactive lymph nodes and tonsils. STING expression was assessed by immunohistochemical methods using diagnostic biopsy specimens obtained prior to treatment. Using an arbitrary 10% cutoff, STING was differentially expressed among T/NK-cell NHLs; positive in 36 out of 38 (95%) cases of ALK+ anaplastic large cell lymphoma (ALCL), 23 out of 37 (62%) ALK-ALCLs, 1 out of 13 (7.7%) angioimmunoblastic T-cell lymphomas, 15 out of 19 (79%) peripheral T-cell lymphomas, not otherwise specified, 20 out of 36 (56%) extranodal NK/T-cell lymphomas of nasal type, 6 out of 7 (86%) T-cell lymphoblastic lymphomas, and 3 out of 4 (75%) mycosis fungoides. STING expression did not correlate with clinicopathological parameters or outcome in these patients with T/NK-cell lymphoma. By contrast, all 265 B-cell NHLs of various types were STING-negative. In addition, STING mRNA levels were very high in 6 out of 7 T-cell NHL cell lines, namely, ALK+ and ALK-ALCL cell lines, and very low or undetectable in 7 B-cell NHL cell lines, suggesting transcriptional downregulation of STING in neoplastic B-cells. At the protein level, using Western blot analysis and immunohistochemistry performed on cell blocks, STING expression was found to be restricted to T-cell NHL cell lines. Taken together, STING expression represents a novel biomarker and therapeutic target in T- and NK-cell lymphomas with direct immunotherapeutic implications since modulators of cGAS–STING activity are already available for clinical use. [ABSTRACT FROM AUTHOR]

Simple Summary: Ablation techniques use extremely hot or cold temperatures to kill small cancers. It is now known that in addition to killing the cancer cells, the ablation treatment may stimulate an immune response in patients against the cancer cells, acting like a vaccine. As a result, there is now interest in combining ablation together with drugs that target the immune system of patients with cancer to enhance the effects of both treatments. In order to develop such combined treatments and test them in clinical trials, we need to understand more about their effects so trials can be optimally designed to be most effective. We have analysed 164 circulating proteins in the blood from patients with small renal tumours undergoing ablation treatment to understand more about the effects of ablation on the patient, both at the level of the effects on the cancer cells and the response of the patients. Further biological understanding of the immune and inflammatory responses following ablation is critical to the rational development of combination ablation-immunotherapies. Our pilot exploratory study evaluated the circulating plasma protein profiles after image-guided ablation (IGA) of small renal masses to determine the resultant systemic effects and provide insight into impact both on the tumour and immune system. Patients undergoing cryotherapy (CRYO), radiofrequency ablation (RFA) or microwave ablation (MWA) for small renal tumours were recruited. Blood samples were obtained at four timepoints; two baselines prior to IGA and at 24 h and 1–3 months post-IGA, and a panel of 164 proteins measured. Of 55 patients recruited, 35 underwent ablation (25 CRYO, 8 RFA, 2 MWA) and biomarker measurements. The most marked changes were 24 h post-CRYO, with 29 proteins increasing and 18 decreasing significantly, principally cytokines and proteins involved in regulating inflammation, danger-associated molecular patterns (DAMPs), cell proliferation, hypoxic response, apoptosis and migration. Intra-individual variation was low but inter-individual variation was apparent, for example all patients showed increases in IL-6 (1.7 to 29-fold) but only 50% in CD27. Functional annotation analysis highlighted immune/inflammation and cell proliferation/angiogenesis-related clusters, with interaction networks around IL-6, IL-10, VEGF-A and several chemokines. Increases in IL-8, IL-6, and CCL23 correlated with cryoprobe number (p = 0.01, rs = 0.546; p = 0.009, rs = 0.5515; p = 0.005, rs = 0.5873, respectively). This initial data provide further insights into ablation-induced biological changes of relevance in informing trial design of immunotherapies combined with ablation. [ABSTRACT FROM AUTHOR]

Simple Summary: SARS-CoV-2 infection has been associated with broad dysregulation of the circulating immune system and inflammation that could persist for a long period. Chronic inflammation has been shown to play a significant role in cancer development and progression. Here we showed that several immune-related factors were altered in cancer patients who had previously been exposed to the virus. Several of these immune factors observed to be elevated even after 3 months of infection are also tumour-promoting factors. The results of this study suggest that we need to pay more attention to cancer patients who have recovered from COVID-19 for any increased rate of cancer progression. Cytokines, chemokines, and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to a worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically, whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n = 54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n = 42). Of the 35 CCGs, 19 were common to both the solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-α, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n = 52). Of these, TNF-α, IFN-β, TSLP, and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data demonstrate a need for increased vigilance for haematological malignancy patients as a part of long COVID follow-up. [ABSTRACT FROM AUTHOR]

Simple Summary: In light of expanding incidences of keratinocyte carcinoma (KC) with many patients developing multiple tumors, the demand for new treatment modalities is high. With the approval of cemplimab for locally advanced and metastasizing basal cell carcinoma and squamous cell carcinoma, KC is now included as an indication for systemic immunotherapy. At present, however, systemic KC therapy remains limited by the severe side effects associated with treatment. Immunotherapy might be more broadly applied if locally administered. Localized to the skin, KCs are easily accessible to topical drugs and physical interventions such as laser. There is an increasing appreciation of lasers' potential to activate an immune response. Further enhancement of the laser-based immune activation might be obtained by combining laser and immunotherapeutic agents, known as laser immunotherapy. In search of new treatment modalities for KC and aiming to broaden the field of KC immunotherapy, this review discusses the current literature on immune activation following both laser monotherapy and laser immunotherapy. The role of the immune system in cancer growth is well recognized and the development of immunotherapy represents a breakthrough in cancer treatment. Recently, the use of systemic immunotherapy was extended to keratinocyte carcinoma (KC), specifically locally advanced and metastasizing basal and squamous cell carcinoma. However, since most KC lesions are non-aggressive, systemic treatment with associated side effects is rarely justified. Conversely, topical immunotherapy with imiquimod remains restricted to premalignant and superficial lesions. Use of laser in the treatment of KC has evolved from physical tumor destruction and laser-assisted drug delivery to laser-mediated immune modulation. Evidence indicates that laser monotherapy can lead to immune cell infiltration, tumor reduction and resistance to tumor re-inoculation. Combining laser with immunotherapeutic agents, termed laser immunotherapy (LIT), may further potentiate immune activation and tumor response. Studies on LIT show not only direct anti-tumor effects but systemic adaptive immunity, illustrated by the prevention of tumor recurrence and regression in distant untreated tumors. These findings imply a therapeutic potential for both local and metastatic disease. This work provides rationales for immune-based treatment of KC and presents the current status of KC immunotherapy. Aiming to expand the field of KC immunotherapy, the review discusses the literature on immune activation following laser monotherapy and LIT. [ABSTRACT FROM AUTHOR]

Simple Summary: Transmembrane proteins (TMEM) are a large group of integral membrane proteins whose molecular and biological functions are not fully understood. It is known that some of them are involved in tumor formation and metastasis. Here, we performed a panel of TCGA data analyses to investigate the role of different TMEM genes in head and neck squamous cell carcinoma (HNSCC) and define their potential as biomarkers. Based on changes in the expression levels in HNSCC tumors, we selected four TMEM genes: ANO1, TMEM156, TMEM173, and TMEM213 and associated them with patient survival. We also demonstrated that the expression of those TMEMs highly correlates with the enrichment of genes involved in numerous biological processes, especially metastasis formation and immune response. Thus, we propose ANO1, TMEM156, TMEM173, and TMEM213 as new biomarkers and potential targets for personalized therapy of HNSCC. Background: Transmembrane proteins (TMEM) constitute a large family of proteins spanning the entirety of the lipid bilayer. However, there is still a lack of knowledge about their function or mechanism of action. In this study, we analyzed the expression of selected TMEM genes in patients with head and neck squamous cell carcinoma (HNSCC) to learn their role in tumor formation and metastasis. Materials and Methods: Using TCGA data, we analyzed the expression levels of different TMEMs in both normal and tumor samples and compared those two groups depending on clinical-pathological parameters. We selected four TMEMs whose expression was highly correlated with patient survival status and subjected them to further analysis. The pathway analysis using REACTOME and the gene set enrichment analysis (GSEA) were performed to evaluate the association of those TMEMs with genes involved in hallmarks of cancer as well as in oncogenic and immune-related pathways. In addition, the fractions of different immune cell subpopulations depending on TMEM expression were estimated in analyzed patients. The results for selected TMEMs were validated using GEO data. All analyses were performed using the R package, Statistica, and Graphpad Prism. Results: We demonstrated that 73% of the analyzed TMEMs were dysregulated in HNSCC and depended on tumor localization, smoking, alcohol consumption, or HPV infection. The expression levels of ANO1, TMEM156, TMEM173, and TMEM213 correlated with patient survival. The four TMEMs were also upregulated in HPV-positive patients. The elevated expression of those TMEMs correlated with the enrichment of genes involved in cancer-related processes, including immune response. Specifically, overexpression of TMEM156 and TMEM173 was associated with immune cell mobilization and better survival rates, while the elevated ANO1 expression was linked with metastasis formation and worse survival. Conclusions: In this work, we performed a panel of in silico analyses to discover the role of TMEMs in head and neck squamous cell carcinoma. We found that ANO1, TMEM156, TMEM173, and TMEM213 correlated with clinical status and immune responses in HNSCC patients, pointing them as biomarkers for a better prognosis and treatment. This is the first study describing such the role of TMEMs in HNSCC. Future clinical trials should confirm the potential of those genes as targets for personalized therapy of HNSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Dietary restriction regimens, such as caloric restriction (CR), in the initiation and development of cancers has been studied using biological models and traditionally considers CR as anti-cancerogenic. However, the experimental, clinical facts and conclusions are controversial. CR-induced molecular and cellular mechanisms and pro-oncogenic pathways have not been systematically studied, leaving therapeutic benefits unclear. Here, using systems biology and deep data analysis approach, we study the CR-induced molecular pathway switches and cell-type context-specific responses known to underly early pre-malignant states in mouse and human mucosa. We identify the genes and energy-restricted networks associated with pre-malignant state metabolic reprogramming in normal stem cells and epithelial cell cycle activation, leading to telomere ends misbalance and immune response depletion. We define the changes in tumor suppressor and oncogenic pathways which may precede intestinal mucosa lesion development. This work will aid in the near future to define critical biomarkers for earlier detection and risk of adenomas and colorectal cancer. Systems cancer biology analysis of calorie restriction (CR) mechanisms and pathways has not been carried out, leaving therapeutic benefits unclear. Using metadata analysis, we studied gene expression changes in normal mouse duodenum mucosa (DM) response to short-term (2-weeks) 25% CR as a biological model. Our results indicate cancer-associated genes consist of 26% of 467 CR responding differential expressed genes (DEGs). The DEGs were enriched with over-expressed cell cycle, oncogenes, and metabolic reprogramming pathways that determine tissue-specific tumorigenesis, cancer, and stem cell activation; tumor suppressors and apoptosis genes were under-expressed. DEG enrichments suggest telomeric maintenance misbalance and metabolic pathway activation playing dual (anti-cancer and pro-oncogenic) roles. The aberrant DEG profile of DM epithelial cells is found within CR-induced overexpression of Paneth cells and is coordinated significantly across GI tract tissues mucosa. Immune system genes (ISGs) consist of 37% of the total DEGs; the majority of ISGs are suppressed, including cell-autonomous immunity and tumor-immune surveillance. CR induces metabolic reprogramming, suppressing immune mechanics and activating oncogenic pathways. We introduce and argue for our network pro-oncogenic model of the mucosa multicellular tissue response to CR leading to aberrant transcription and pre-malignant states. These findings change the paradigm regarding CR's anti-cancer role, initiating specific treatment target development. This will aid future work to define critical oncogenic pathways preceding intestinal lesion development and biomarkers for earlier adenoma and colorectal cancer detection. [ABSTRACT FROM AUTHOR]

Simple Summary: Human papillomavirus (HPV) infections are responsible for a continually growing number of head and neck cancer (HNC) cases, with the incident rate overtaking that of HPV-related cervical cancers in the United States. Most HPV-related HNC cases arise in the oropharynx, and although they have a better 5-year survival rate than non-HPV-related HNC patients (80% compared to 50%), de-escalating treatment in all HPV(+) patients in an attempt to improve quality of life led to unacceptable results. Studying molecular subtypes of HPV(+) HNC can help to identify treatment regimens tailored to each patient's tumor characteristics. We synthesized information from several studies of HPV(+) HNC subtypes, and describe three main groups that differ by their immune cell content, level of keratinocyte differentiation, degree of epithelial-to-mesenchymal transition, probability of HPV integration, oxidoreductase activity and stromal cell (e.g., cancer-associated fibroblast) content. The differences have important implications for local or distant recurrence, treatment response and survival. Until recently, research on the molecular signatures of Human papillomavirus (HPV)-associated head and neck cancers mainly focused on their differences with respect to HPV-negative head and neck squamous cell carcinomas (HNSCCs). However, given the continuing high incidence level of HPV-related HNSCC, the time is ripe to characterize the heterogeneity that exists within these cancers. Here, we review research thus far on HPV-positive HNSCC molecular subtypes, and their relationship with clinical characteristics and HPV integration into the host genome. Different omics data including host transcriptomics and epigenomics, as well as HPV characteristics, can provide complementary viewpoints. Keratinization, mesenchymal differentiation, immune signatures, stromal cells and oxidoreductive processes all play important roles. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastasis in general represents the progression phenotype whereby cancer cells break from a malignant primary location and travel to and invade other distant organs. Theoretically, tumor cells that exit the primary tumor might be eliminated by immune cells. The immune system has the ability to recognize and eliminate malignant tumor cells; however, failed immune surveillance contributes to cancer development. Disseminated tumor cells persist and reemerge as a clinically symptomatic disease. How do disseminated tumor cells evade immune surveillance? In this context, tumor/immune system interactions play a key role and are the subject of intense scrutiny. After colonization, the immunosuppressive tumor microenvironments of metastatic lesions promote tumor growth and worsen prognosis. Here, we discuss scientific advances relating to the interaction between disseminated tumor cells and the immune cells in tissue-specific tumor microenvironments. Most cancer-related deaths are a consequence of metastases, a series of linear events, notably the invasion–metastasis cascade. The current understanding of cancer immune surveillance derives from studies in primary tumors, but disseminated cancer cells acquire mutations and, in some cases, appear to progress independently after spreading from primary sites. An early step in this process is micrometastatic dissemination. As such, the equilibrium between the immune system and disseminated cancer cells controls the fate of the cancer. Immune checkpoint inhibitors (ICIs) exhibit significant clinical activity in patients, but the efficacy of ICIs depends on both the tumor and its microenvironment. Data often suggest that disseminated cancer cells are not adequately targeted by the immune system. In this review, we summarize the main basic findings of immune responses against disseminated tumor cells and their organ-specific characteristics. Such studies may provide new directions for cancer immune therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Treating older patients with (breast) cancer is a major challenge. On the one hand, older persons are more vulnerable to side effects of therapy, and over-treatment should be avoided. On the other hand, under-treatment (which is common in the elderly) can lead to worse survival and quality of life as well. Benefits of therapy and risk of (sometimes life threatening) toxicity should be carefully balanced. There is an urgent need for robust markers that reflect the body's biological age and could aid in outlining optimal individual treatment regimens. Here we investigated whether age/frailty and characteristics of the tumor immune infiltrate are mirrored in specific blood biomarker combinations. Several three-biomarker panels were able to categorize patients quite efficiently, especially in terms of their clinical frailty status. Background: Immune/senescence-related host factors play a pivotal role in numerous biological and pathological process like aging, frailty and cancer. The assessment of these host factors via robust, non-invasive, and easy-to-measure blood biomarkers could improve insights in these processes. Here, we investigated in a series of breast cancer patients in which way single circulating biomarkers or biomarker panels relate to chronological age, frailty status, and tumor-associated inflammatory microenvironment. Methods: An extensive panel of blood immune/senescence markers and the tumor immune infiltrate was studied in young, middle-aged, and old patients with an early invasive hormone-sensitive, HER2-negative breast cancer. In the old group, clinical frailty was estimated via the G8-scores. Results: Several three-blood biomarker panels proved to be able to separate old chronological age from young age very efficiently. Clinically more important, several three-blood biomarker panels were strongly associated with clinical frailty. Performance of blood biomarker panels for prediction of the tumor immune infiltrate was lower. Conclusion: Immune/senescence blood biomarker panels strongly correlate with chronological age, and clinically more importantly with frailty status in early breast cancer patients. They require further investigation on their ability to provide a more complete picture on clinical frailty status and direct personalized therapy in older persons. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of our study was to evaluate the predictive performance of transcriptomic biomarkers to immune response. The study collected 22 transcriptomic biomarkers and constructed multiple benchmark datasets to evaluate their predictive performance of immune checkpoint blockade (ICB) response in pre-treatment patients with distinct ICB agents in diverse cancers. We found "Immune-checkpoint molecule" biomarkers PD-L1, PD-L2, CTLA-4 and IMPRES and the "Effector molecule" biomarker CYT showed significant associations with ICB response and clinical outcomes. These immune-checkpoint biomarkers and another immune effector IFN-gamma presented predictive ability in melanoma, urothelial cancer and clear cell renal-cell cancer. Interestingly, for anti-PD-1 therapy and anti-CTLA-4 therapy, the top-performing response biomarkers were usually mutually exclusive even though in the same biomarker category and most of biomarkers with outstanding predictive power were observed in patients with combined anti-PD-1 and anti-CTLA-4 therapy. Background: Immune checkpoint blockade (ICB) therapy has yielded successful clinical responses in treatment of a minority of patients in certain cancer types. Substantial efforts were made to establish biomarkers for predicting responsiveness to ICB. However, the systematic assessment of these ICB response biomarkers remains insufficient. Methods: We collected 22 transcriptome-based biomarkers for ICB response and constructed multiple benchmark datasets to evaluate the associations with clinical response, predictive performance, and clinical efficacy of them in pre-treatment patients with distinct ICB agents in diverse cancers. Results: Overall, "Immune-checkpoint molecule" biomarkers PD-L1, PD-L2, CTLA-4 and IMPRES and the "Effector molecule" biomarker CYT showed significant associations with ICB response and clinical outcomes. These immune-checkpoint biomarkers and another immune effector IFN-gamma presented predictive ability in melanoma, urothelial cancer (UC) and clear cell renal-cell cancer (ccRCC). In non-small cell lung cancer (NSCLC), only PD-L2 and CTLA-4 showed preferable correlation with clinical response. Under different ICB therapies, the top-performing biomarkers were usually mutually exclusive in patients with anti-PD-1 and anti-CTLA-4 therapy, and most of biomarkers presented outstanding predictive power in patients with combined anti-PD-1 and anti-CTLA-4 therapy. Conclusions: Our results show these biomarkers had different performance in predicting ICB response across distinct ICB agents in diverse cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Oncolytic viruses show great promise as anticancer agents by simultaneously lysing cancer cells while stimulating innate and adaptive immune responses. However, the extent to which the adaptive immune system contributes to overall efficacy alongside oncolytic viruses is, in part, dependent on the compliance of cancer cells to present antigens correctly. Dysregulation of any part of the antigen presentation machinery provides a strong selection pressure for immune escape. In this review, we consider the key immunological factors that might be measured to allow for the optimum deployment of oncolytic viruses for effective cancer therapy. Dysregulation of HLA (human leukocyte antigen) function is increasingly recognized as a common escape mechanism for cancers subject to the pressures exerted by immunosurveillance or immunotherapeutic interventions. Oncolytic viruses have the potential to counter this resistance by upregulating HLA expression or encouraging an HLA-independent immunological responses. However, to achieve the best therapeutic outcomes, a prospective understanding of the HLA phenotype of cancer patients is required to match them to the characteristics of different oncolytic strategies. Here, we consider the spectrum of immune competence observed in clinical disease and discuss how it can be best addressed using this novel and powerful treatment approach. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer stem cells (CSCs) are considered responsible for the maintenance, metastasis, and recurrence of various tumors. Here, we isolated a novel CSCs, TW-1, which can self-renew, differentiate and resistant to sorafenib. We also established novel orthotopic and metastasis models in immunocompetent rats with TW-1. These immunocompetent animal model can provide a normal physiological condition for anti-cancer drug screening. Using machine learning, we predicted HCC (AUCs > 0.9) with eight biomarkers including 6 highly expressed in TW-1/HTC and 2 well-known biomarkers from recent HCC studies. In conclusion, our results showed that TW-1 was a novel rat CSC line, and the animal model established with TW-1, is not only useful for the study of metastasis of HCC but also preclinical cancer drug screening. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. Cancer stem cells (CSCs) are responsible for the maintenance, metastasis, and relapse of various tumors. The effects of CSCs on the tumorigenesis of HCC are still not fully understood, however. We have recently established two new rat HCC cell lines HTC and TW-1, which we isolated from diethylnitrosamine-induced rat liver cancer. Results showed that TW-1 expressed the genetic markers of CSCs, including CD133, GSTP1, CD44, CD90, and EpCAM. Moreover, TW-1 showed higher tolerance to sorafenib than HTC did. In addition, tumorigenesis and metastasis were observed in nude mice and wild-type rats with TW-1 xenografts. Finally, we combined highly expressed genes in TW-1/HTC with well-known biomarkers from recent HCC studies to predict HCC-related biomarkers and able to identify HCC with AUCs > 0.9 after machine learning. These results indicated that TW-1 was a novel rat CSC line, and the mice or rat models we established with TW-1 has great potential on HCC studies in the future. [ABSTRACT FROM AUTHOR]

Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m 2 /bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20 + cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a major cause of cancer-related death in the world. Emerging evidence suggests that the clinical success of conventional chemotherapy does not merely rely on cell toxicity, but also results from the restoration of tumor immune surveillance. Anti-tumor immune response can be primed by immunogenic cell death (ICD), a form of apoptosis associated with endoplasmic reticulum stress (ERS) induction and the expression/release of specific damage-associated molecular patterns (DAMPs). Unfortunately, a limited number of ICD inducers have been identified so far. The anti-helmintic drug rafoxanide has recently showed anti-tumor activity in different cancer types, including CRC. As such latter effects relied on ERS activation, we here investigated whether rafoxanide could promote ICD of CRC cells. The potential of rafoxanide to induce ICD-related DAMPs in both human and mouse CRC cells was assessed by flow-cytometry, chemiluminescent assay and ELISA. In addition, the immunogenic potential of rafoxanide was assessed in vivo using a vaccination assay. Rafoxanide induced all the main DAMPs (ecto-calreticulin exposure, adenosine triphosphate (ATP)/high mobility group box 1 (HMGB1) release) required for ICD. We observed a marked increase of tumor-free survival among immunocompetent mice immunized with rafoxanide-treated dying tumor cells as compared with sham. Altogether, our data indicate rafoxanide as a bona fide ICD inducer. [ABSTRACT FROM AUTHOR]

All-trans retinoic acid (ATRA), a recognized differentiating agent, has significant potential in the personalized/stratified treatment of breast cancer. The present study reports on the molecular mechanisms underlying the anti-tumor activity of ATRA in breast cancer. The work is based on transcriptomic experiments performed on ATRA-treated breast cancer cell-lines, short-term tissue cultures of patient-derived mammary-tumors and a xenograft model. ATRA upregulates gene networks involved in interferon-responses, immune-modulation and antigen-presentation in retinoid-sensitive cells and tumors characterized by poor immunogenicity. ATRA-dependent upregulation of these gene networks is caused by a viral mimicry process, involving the activation of endogenous retroviruses. ATRA induces a non-canonical type of viral mimicry, which results in increased expression of the IRF1 (Interferon Responsive Factor 1) transcription factor and the DTX3L (Deltex-E3-Ubiquitin-Ligase-3L) downstream effector. Functional knockdown studies indicate that IRF1 and DTX3L are part of a negative feedback loop controlling ATRA-dependent growth inhibition of breast cancer cells. The study is of relevance from a clinical/therapeutic perspective. In fact, ATRA stimulates processes controlling the sensitivity to immuno-modulatory drugs, such as immune-checkpoint-inhibitors. This suggests that ATRA and immunotherapeutic agents represent rational combinations for the personalized treatment of breast cancer. Remarkably, ATRA-sensitivity seems to be relatively high in immune-cold mammary tumors, which are generally resistant to immunotherapy. [ABSTRACT FROM AUTHOR]

The role of CD47 and PD-L1 expression on circulating tumor cells (CTCs) remains unclear, and it is currently unknown whether their distribution varies between the blood and tumor tissue in breast cancer (BC). In this study, CD47 and PD-L1 expression was investigated a) on peripheral blood mononuclear cell (PBMC) cytospins from early (n = 100) and metastatic (n = 98) BC patients, by triple immunofluorescence for CD47/PD-L1/Cytokeratins, and b) on matched primary and/or metastatic tumor tissue from CTC-positive patients using immunohistochemistry. CD47+and/orPD-L1+ CTCs were detected in 11%, 16.9%, and 29.6% of early, recurrent, and de novo metastatic patients (p = 0.016). In metastatic disease, CD47highand/orPD-L1high CTCs were associated with disease progression (p = 0.005) and shorter progression-free survival (PFS) (p = 0.010), and independently predicted for an increased risk of relapse (HR: 2.719; p = 0.008) and death (HR: 2.398; p = 0.034). PD-L1 expression rates differed between CTCs and tissue tumor cells and between peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) (positive concordance of 3.8% and 4%, respectively). CD47 expression also differed between CTCs and tumor cells (positive concordance of 11.5%). In conclusion, CTCs expressing CD47 and PD-L1 have independent poor prognostic implications in metastatic BC, indicating a potential role of innate and adaptive immune evasion mechanisms in their metastatic potential. The clinical value of the parallel assessment of the peripheral and local immune response merits further evaluation in BC. [ABSTRACT FROM AUTHOR]

A Pancreatic cancer is a notorious malignant neoplasm with an extremely poor prognosis. Current standard of care is rarely effective against late-stage pancreatic cancer. In this study, we assessed nanopulse stimulation (NPS) as a local treatment for pancreatic cancer in a syngeneic mouse Pan02 pancreatic cancer model and characterized corresponding changes in the immune profile. A single NPS treatment either achieved complete tumor regression or prolonged overall survival in animals with partial tumor regression. While this is very encouraging, we also explored if this local ablation effect could also result in immune stimulation, as was observed when NPS led to the induction of immune-mediated protection from a second tumor challenge in orthotopic mouse breast and rat liver cancer models. In the Pan02 model, there were insufficient abscopal effects (1/10) and vaccine-like protective effects (1/15) suggesting that NPS-induced immune mechanisms in this model were limited. To evaluate this further, the immune landscape was analyzed. The numbers of both T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSCs) in blood were significantly reduced, but memory (CD44+) T-cells were absent. Furthermore, the numbers of Tregs and MDSCs did not reduce in spleens compared to tumor-bearing mice. Very few T-cells, but large numbers of MDSCs were present in the NPS treated tumor microenvironment (TME). The number of dendritic cells in the TME was increased and multiple activation markers were upregulated following NPS treatment. Overall, NPS treatments used here are effective for pancreatic tumor ablation, but require further optimization for induction of immunity or the need to include effective combinational NPS therapeutic strategy for pancreatic cancer. [ABSTRACT FROM AUTHOR]