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Simple Summary: As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, extracellular matrix (ECM), and soluble molecules forming the widely recognized tumor microenvironment. The main components of the tumor microenvironment include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), ECM, and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). The tumor microenvironment has been suggested to play a central role in tumor progression and treatment resistance. Accumulated evidence indicates that tumor maintenance, progression, and treatment resistance are determined by components of the microenvironment. Thus, targeting the components of the tumor microenvironment may have a therapeutic impact on melanoma treatment. The main topic of this paper deals with the main components of the tumor microenvironment and their impact as therapeutic targets in melanoma treatment. The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer in the head and neck region (HNSCC) is exponentially increasing due to human papillomavirus (HPV) infections. This paper helps us to understand the complexity of the inflammatory networks and the mechanisms of immune evasion in HPV+ HNSCC to open up new avenues and drive the discovery of useful tools to be translated clinically in the screening and treatment of these cases, especially to overcome resistance and improve patients' quality of life. Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignancies which have shown exponential incidence in the last two decades especially due to human papillomavirus (HPV) infection. The HPV family comprises more than 100 types of viruses with HPV16 and HPV18 being the most prevalent strains in HNSCC. Literature data reveal that the mutation profile as well as the response to chemotherapy and radiotherapy are distinct among HPV+ versus HPV-negative tumors. Furthermore, the presence of the virus induces activation of an immune response, in particular the recruitment of specific antiviral T lymphocytes to tumor sites. These T cells when activated produce soluble factors including cytokines and chemokines capable of modifying the local immune tumor microenvironment and impact on tumor response to the treatment. In this comprehensive review we investigated current knowledge on how the presence of an HPV can modify the inflammatory response systemically and within the tumor microenvironment's immunological responses, thereby impacting on disease prognosis and survival. We highlighted the research gaps and emerging approaches necessary to discover novel immunotherapeutic targets for HPV-associated HNSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: It is difficult to predict which patients with non-metastatic clear cell renal cell carcinoma (ccRCC) will develop metastatic disease after nephrectomy. Recent studies suggest that immune cell infiltration within ccRCC tumors may impact tumor progression. This study assessed the number and type of immune cells in non-metastatic ccRCC tumors that were surgically removed and their ability to predict which patients developed metastatic disease. We found that higher levels of a specific immune cell (CD8+ T cells) were linked to a lower risk of progressive disease. Patients who did progress had more exhausted CD8+ T cells in the tumor microenvironment. Additionally, our study design accounted for tumor heterogeneity by sampling tumors in multiple locations and showed differences in the spatial distribution of CD8+ T cells in tumors that progressed to metastatic disease. With further validation, this study shows that CD8+ T cell infiltration within ccRCC tumors could be used as a prognostic biomarker to predict progression to metastatic disease. Predicting which patients will progress to metastatic disease after surgery for non-metastatic clear cell renal cell carcinoma (ccRCC) is difficult; however, recent data suggest that tumor immune cell infiltration could be used as a biomarker. We evaluated the quantity and type of immune cells infiltrating ccRCC tumors for associations with metastatic progression following attempted curative surgery. We quantified immune cell densities in the tumor microenvironment and validated our findings in two independent patient cohorts with multi-region sampling to investigate the impact of heterogeneity on prognostic accuracy. For non-metastatic ccRCC, increased CD8+ T cell infiltration was associated with a reduced likelihood of progression to metastatic disease. Interestingly, patients who progressed to metastatic disease also had increased percentages of exhausted CD8+ T cells. Finally, we evaluated the spatial heterogeneity of the immune infiltration and demonstrated that patients without metastatic progression had CD8+ T cells in closer proximity to ccRCC cells. These data strengthen the evidence for CD8+ T cell infiltration as a prognostic biomarker in non-metastatic ccRCC and demonstrate that multi-region sampling may be necessary to fully characterize immune infiltration within heterogeneous tumors. Tumor CD8+ T cell infiltration should be investigated as a biomarker in adjuvant systemic therapy clinical trials for high-risk non-metastatic RCC. [ABSTRACT FROM AUTHOR]

Simple Summary: (CAR)-T cell-based therapies have achieved substantial success against different haematological malignancies. However, results for solid tumours have been limited up to now, in part due to the fact that the immunosuppressive tumour microenvironment inactivates CAR-T cell clones. In this paper we study mathematically the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using computer simulations, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study in silico, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. This strategy lead in our simulations to the expansion of the CAR-T cells injected and the production of a massive army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. Thus, our proposed strategy could provide a way to develop successful CAR-T cell therapies against solid tumours. Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) are the main primary brain tumors in adults. The role of the immune system in the progression of GBM is still largely under-evaluated. Here, we assessed the distribution of multiple immune biomarkers in a handful of coupled primary and recurrent GBM using both classical immunochemistry and Nanostring Geomix Digital spatial profiling. We observed an absence of correlation between the immune landscape during the evolution of GBM, both in the center and the periphery of the tumor. However, global analyses indicate differential localization of HLA-DR and B7-H3 between primary and recurrent GBM. Only a minority of patients with glioblastoma (GBM) respond to immunotherapy, and always only partially. There is a lack of knowledge on immune distribution in GBM and in its tumor microenvironment (TME). To address the question, we used paired primary and recurrent tumors from GBM patients to study the composition and the evolution of the immune landscape upon treatment. We studied the expression of a handful of immune markers (CD3, CD8, CD68, PD-L1 and PD-1) in GBM tissues in 15 paired primary and recurrent GBM. In five selected patients, we used Nanostring Digital Spatial Profiling (DSP) to obtain simultaneous assessments of multiple biomarkers both within the tumor and the microenvironment in paired primary and recurrent GBM. Our results suggest that the evolution of the immune landscape between paired primary and recurrent GBM tumors is highly heterogeneous. However, our study identifies B3-H7 and HLA-DR as potential targets in primary and recurrent GBM. Spatial profiling of immune markers from matched primary and recurrent GBM shows a nonlinear complex evolution during the progression of cancer. Nonetheless, our study demonstrated a global increase in macrophages, and revealed differential localization of some markers, such as B7-H3 and HLA-DR, between GBM and its TME. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy, and it has greatly expanded our knowledge of anticancer immunity and has introduced breakthroughs in cancer therapy. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. This review provides an overview of recent advances in cellular and molecular factors within the tumor microenvironment (TME) to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies for cancer immunotherapy. The in-depth exploration of complexity within the TME allows for the improvement of therapeutic efficacy and highlights its contribution to cancer immunotherapy. Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The ubiquitous protein kinase CK2 has been demonstrated to be overexpressed in a number of human tumours. This enzyme is composed of two catalytic α or α' subunits and a dimer of β regulatory subunits whose expression levels are probably implicated in CK2 regulation. Several recent papers reported that unbalanced expression of CK2 subunits is sufficient to drive epithelial to mesenchymal transition, a process involved in cancer invasion and metastasis. Herein, through transcriptomic and miRNA analysis together with comparison of cellular properties between wild type and CKβ-knock-down MCF10A cells, we show that down-regulation of CKβ subunit in mammary epithelial cells induces the acquisition of stem cell-like properties associated with perturbed polarity, CD44high/CD24low antigenic phenotype and the ability to grow under anchorage-independent conditions. These data demonstrate that a CK2β level establishes a critical cell fate threshold in the control of epithelial cell plasticity. Thus, this regulatory subunit functions as a nodal protein to maintain an epithelial phenotype and its depletion drives breast cell stemness. [ABSTRACT FROM AUTHOR]

Simple Summary: Metabolic reprogramming is one of tumor and immune cells' most significant metabolic alterations. Moreover, metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), the mammalian target of rapamycin (mTOR), can induce growth, proliferation, and angiogenesis of tumor cells. Therefore, inhibiting these metabolic pathways can be considered a potential therapeutic strategy in human malignancies. On the other hand, according to previous studies, pharmacological inhibiting of metabolic pathways using dual-pathway inhibitors can considerably inhibit tumor growth and progression, more than suppressing each pathway separately. This review aims to summarize the latest metabolic interventions by dual pathway inhibitors and discuss the achievements and limitations of this therapeutic tactic. The metabolism of tumors and immune cells in the tumor microenvironment (TME) can affect the fate of cancer and immune responses. Metabolic reprogramming can occur following the activation of metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR). Moreover, various tumor-derived immunosuppressive metabolites following metabolic reprogramming also affect antitumor immune responses. Evidence shows that intervention in the metabolic pathways of tumors or immune cells can be an attractive and novel treatment option for cancer. For instance, administrating inhibitors of various signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), can improve T cell-mediated antitumor immune responses. However, dual pathway inhibitors can significantly suppress tumor growth more than they inhibit each pathway separately. This review discusses the latest metabolic interventions by dual pathway inhibitors as well as the advantages and disadvantages of this therapeutic approach. [ABSTRACT FROM AUTHOR]

Simple Summary: Combination of radiotherapy and immunotherapy to antagonize tumors is one of hotspot issues currently. Immunotherapy can effectively alleviate the non-lasting effect of radiotherapy and tumor recurrence. Local radiotherapy can mobilize immune cells into tumor microenvironment and make tumors unable to escape from immune supervision. Therefore, the radio-immunotherapy achieves better curative effects on cancer patients. We have reviewed the regulation of multiple immune cells with different functions by radiotherapy, as well as the mechanism research and clinical outcomes combined with immune checkpoint inhibitors for cancer treatment, which provides new insights in the treatment strategies for certain types of cancer patients in clinic. Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the "hot" tumors gradually turn to "cold". With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic. [ABSTRACT FROM AUTHOR]

Simple Summary: Follicular lymphoma is the most common type of indolent non-Hodgkin lymphoma and is characterized by its heterogeneity and variable course. In addition to tumor cells, the immune microenvironment plays a fundamental role in the pathogenesis of the disease. Despite advances in treatment, responses vary among patients, and outcomes are often unpredictable: a subset of high-risk patients will be refractory to standard treatments or will develop a high-grade histology. In this review, we try to understand the crosstalk between follicular lymphoma B-cells and the tumor microenvironment as well as its impact on prognosis and the risk of transformation. We also highlight recent findings related to novel therapies developed to treat this complex disease, in which genetic mutations and microenvironment cells play a key role. Follicular lymphomas (FL) are neoplasms that resemble normal germinal center (GC) B-cells. Normal GC and neoplastic follicles contain non-neoplastic cells such as T-cells, follicular dendritic cells, cancer associated fibroblasts, and macrophages, which define the tumor microenvironment (TME), which itself is an essential factor in tumor cell survival. The main characteristics of the TME in FL are an increased number of follicular regulatory T-cells (Treg) and follicular helper T-cells (Tfh), M2-polarization of macrophages, and the development of a nodular network by stromal cells that creates a suitable niche for tumor growth. All of them play important roles in tumor angiogenesis, inhibition of apoptosis, and immune evasion, which are key factors in tumor progression and transformation risk. Based on these findings, novel therapies have been developed to target specific mutations present in the TME cells, restore immune suppression, and modulate TME. [ABSTRACT FROM AUTHOR]

Simple Summary: Current studies aim to target tumor-associated macrophages (TAMs) to alleviate immunosuppression and inhibit tumor growth. However, the specific mechanisms that drive TAMs to impede T cell migration into and within tumors are still unclear. Here, we found that after pancreatic ductal adenocarcinoma (PDAC)-bearing mice were treated with clodronate liposomes, the numbers of BrdU-incorporated and Ki-67+-proliferating macrophages were reduced, which might be maintained by local proliferation. Clodronate liposomes treatment could alter the macrophages that foster CD8+ T cell infiltration, promote CD8+ T cell spatial redistribution in tumors, and suppress PDAC growth. This study suggests that depletion of macrophages may increase CD8+ T cell infiltration and promote CD8+ T cell spatial redistribution in tumors, contributing to the antitumor effect. Tumor-associated macrophages (TAMs) play crucial roles in cancer progression, but the contributions and regulation of different macrophage subpopulations remain unclear. Here, we report a high level of TAM infiltration in human and mouse pancreatic ductal adenocarcinoma (PDAC) models and that the targeting of proliferating F4/80+ macrophages facilitated cytotoxic CD8+ T-cell-dependent antitumor immune responses. A well-defined KPC-derived PDAC cell line and the murine Panc02 PDAC cell line were used. Treatment of PDAC-bearing mice with clodronate liposomes, an agent that chemically depletes macrophages, did not impact macrophage subpopulations in the local tumor microenvironment (TME). However, further investigation using both BrdU and Ki67 to evaluate proliferating cells showed that clodronate liposomes treatment reduced proliferating macrophages in the KPC and Panc02 models. We further evaluated the distance between CD8+ T cells and PanCK+ tumor cells, and clodronate liposomes treatment significantly increased the number of CD8+ T cells in close proximity (<30 µm) to PanCK+ PDAC cells, with increased numbers of tumor-infiltrating IFN-γ+CD8+ T cells. This study suggests that targeting proliferating tumor-infiltrating macrophages may increase CD8+ cytotoxic lymphocyte (CTL) infiltration and facilitate the spatial redistribution of CD8+ T cells in tumors, contributing to the antitumor effect. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcoma is the most common primary bone tumor and has a poor prognosis. Therefore, it is important to understand the mechanism of the development of osteosarcoma to overcome therapy resistance. Several mathematical models have been developed to study the initiation and progression of many cancer types. However, there are currently no mathematical models for the progression of osteosarcoma, to the best of our knowledge. In this work, we develop a data-driven mathematical model to analyze the impact of the immune cell interactions on the growth of osteosarcoma tumors that have distinct immune patterns. Our model provides a foundation for investigating the effect of various treatments on the dynamics of key players in the primary tumor, including immune cells and cytokines, and ultimately the whole tumor. As the immune system has a significant role in tumor progression, in this paper, we develop a data-driven mathematical model to study the interactions between immune cells and the osteosarcoma microenvironment. Osteosarcoma tumors are divided into three clusters based on their relative abundance of immune cells as estimated from their gene expression profiles. We then analyze the tumor progression and effects of the immune system on cancer growth in each cluster. Cluster 3, which had approximately the same number of naive and M2 macrophages, had the slowest tumor growth, and cluster 2, with the highest population of naive macrophages, had the highest cancer population at the steady states. We also found that the fastest growth of cancer occurred when the anti-tumor immune cells and cytokines, including dendritic cells, helper T cells, cytotoxic cells, and IFN- γ , switched from increasing to decreasing, while the dynamics of regulatory T cells switched from decreasing to increasing. Importantly, the most impactful immune parameters on the number of cancer and total cells were the activation and decay rates of the macrophages and regulatory T cells for all clusters. This work presents the first osteosarcoma progression model, which can be later extended to investigate the effectiveness of various osteosarcoma treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer. Immune checkpoint inhibitor (ICI) therapy has made progress in TNBC treatment. PD-L1 expression is a useful biomarker of ICI therapy efficacy. However, tumor-immune microenvironment (TIME) factors, such as immune cell compositions and tumor-infiltrating lymphocyte (TIL) status, also influence tumor immunity. Therefore, it is necessary to seek biomarkers that are associated with multiple aspects of TIME in TNBC. In this study, we developed an immune-related gene prognostic index (IRGPI) with a substantial prognostic value for TNBC. Moreover, the results from multiple cohorts reproducibly demonstrate that IRGPI is significantly associated with immune cell compositions, the exclusion and dysfunction of TILs, as well as PD-1 and PD-L1 expression in TIME. Therefore, IRGPI is a promising biomarker closely related to patient survival and TIME of TNBC and may have a potential effect on the immunotherapy strategy of TNBC. Tumor-immune cell compositions and immune checkpoints comprehensively affect TNBC outcomes. With the significantly improved survival rate of TNBC patients treated with ICI therapies, a biomarker integrating multiple aspects of TIME may have prognostic value for improving the efficacy of ICI therapy. Immune-related hub genes were identified with weighted gene co-expression network analysis and differential gene expression assay using The Cancer Genome Atlas TNBC data set (n = 115). IRGPI was constructed with Cox regression analysis. Immune cell compositions and TIL status were analyzed with CIBERSORT and TIDE. The discovery was validated with the Molecular Taxonomy of Breast Cancer International Consortium data set (n = 196) and a patient cohort from our hospital. Tumor expression or serum concentrations of CCL5, CCL25, or PD-L1 were determined with immunohistochemistry or ELISA. The constructed IRGPI was composed of CCL5 and CCL25 genes and was negatively associated with the patient's survival. IRGPI also predicts the compositions of M0 and M2 macrophages, memory B cells, CD8+ T cells, activated memory CD4 T cells, and the exclusion and dysfunction of TILs, as well as PD-1 and PD-L1 expression of TNBC. IRGPI is a promising biomarker for predicting the prognosis and multiple immune characteristics of TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor microenvironment (TME) in breast cancer plays important roles in tumor behavior and treatment response, making its pathologic assessment critical for disease management. Analysis of the TME is not only limited to research-based technologies but is now incorporated into routine histopathologic reporting for practical clinical application. This review covers the current understanding of the TME of breast cancer, its pathologic assessment relevant for prognostication and treatment strategies, and the cancer therapies that interacts with and/or exploits the TME in breast cancer. As actionable targets are constantly being discovered in the TME, the future approach to breast cancer therapy is likely to combine cancer cell elimination and TME modulation. The tumor microenvironment (TME) in breast cancer comprises local factors, cancer cells, immune cells and stromal cells of the local and distant tissues. The interaction between cancer cells and their microenvironment plays important roles in tumor proliferation, propagation and response to therapies. There is increasing research in exploring and manipulating the non-cancerous components of the TME for breast cancer treatment. As the TME is now increasingly recognized as a treatment target, its pathologic assessment has become a critical component of breast cancer management. The latest WHO classification of tumors of the breast listed stromal response pattern/fibrotic focus as a prognostic factor and includes recommendations on the assessment of tumor infiltrating lymphocytes and PD-1/PD-L1 expression, with therapeutic implications. This review dissects the TME of breast cancer, describes pathologic assessment relevant for prognostication and treatment decision, and details therapeutic options that interacts with and/or exploits the TME in breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Oesophageal cancer rates are increasing rapidly with patients often presenting at an advanced stage. The current approach to treatment involves radiotherapy, chemotherapy, or combination chemoradiotherapy with surgery; however, only a fraction of these patients will achieve meaningful responses. Therefore, there is a need to better understand the tumour and lymph node microenvironments to inform future treatment strategies. This study measured immune markers including immune checkpoint expression in tumour and lymph node tissue in oesophageal cancer patients and patient clinical outcomes, including survival time, response to treatment, and adverse events. We report herein that nodal metastases is of equal prognostic importance to clinical tumour stage and tumour regression grade in OAC and we observed a more immunosuppressive microenvironment in the tumour compared with the lymph node. Response rates to the current gold standards of care for treating oesophageal adenocarcinoma (OAC) remain modest with 15–25% of patients achieving meaningful pathological responses, highlighting the need for novel therapeutic strategies. This study consists of immune, angiogenic, and inflammatory profiling of the tumour microenvironment (TME) and lymph node microenvironment (LNME) in OAC. The prognostic value of nodal involvement and clinicopathological features was compared using a retrospective cohort of OAC patients (n = 702). The expression of inhibitory immune checkpoints by T cells infiltrating tumour-draining lymph nodes (TDLNs) and tumour tissue post-chemo(radio)therapy at surgical resection was assessed by flow cytometry. Nodal metastases is of equal prognostic importance to clinical tumour stage and tumour regression grade (TRG) in OAC. The TME exhibited a greater immuno-suppressive phenotype than the LNME. Our data suggests that blockade of these checkpoints may have a therapeutic rationale for boosting response rates in OAC. [ABSTRACT FROM AUTHOR]

Simple Summary: Preclinical studies have shown that cold stress results in the activation of thermogenesis and an increased tumor growth rate in mice. This study aimed to investigate the clinical relevance of these laboratory findings in patients with triple-negative breast cancer using publicly available large cohorts. Triple-negative breast cancers with high thermogenesis were found to have a pro-tumorigenic immune microenvironment, which may explain the trend towards poor survival observed in this group. This study investigated thermogenesis as a biomarker to predict clinical outcomes, and may pave the way to test novel therapeutics to improve the outcomes of this breast cancer subtype. Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression. [ABSTRACT FROM AUTHOR]

Simple Summary: The immune response against cancer is generated by effector T cells, among them cytotoxic CD8+ T cells that destroy cancer cells and helper CD4+ T cells that mediate and support the immune response. This antitumor function of T cells is tightly regulated by a particular subset of CD4+ T cells, named regulatory T cells (Tregs), through different mechanisms. Even if the complete inhibition of Tregs would be extremely harmful due to their tolerogenic role in impeding autoimmune diseases in the periphery, the targeted blockade of their accumulation at tumor sites or their targeted depletion represent a major therapeutic challenge. This review focuses on the mechanisms favoring Treg recruitment, expansion and stabilization in the tumor microenvironment and the therapeutic strategies developed to block these mechanisms. Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs' deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4+ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues. [ABSTRACT FROM AUTHOR]

Simple Summary: Wilms' tumor (WT) is the most common childhood renal tumor accounting for approximately 7% of childhood malignancies. The overall survival rate for patients with favorable histology is greater than 90% while the survival rate for patients with poor prognostic factors is around 50%. The current treatments consist in a combination of surgery and chemotherapy or radiotherapy in high risk patients. Such treatments are responsible for significant adverse effects requiring long-term monitoring. Thus, a main challenge in WT treatment is the development of novel therapeutic strategies to eliminate or minimize the adverse effects. The characterization of an immune environment could allow the identification of new therapeutic targets. Herein we studied the interaction between WT and innate immune cells, in particular NK cells and monocytes. Although WT are highly susceptible to NK-mediated lysis, the detection of immunoregulatory activity of WT tumor cells on NK cells and also on monocytes could offer novel cellular and molecular targets for an efficacious immunotherapy of WT. The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm's Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56+/CD133−) or an epithelial (CD56−/CD133+) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression. [ABSTRACT FROM AUTHOR]

Despite the progress during the last decade, patients with advanced gastric and esophageal cancers still have poor prognosis. Finding optimal therapeutic strategies represents an unmet need in this field. Several prognostic and predictive factors have been evaluated and may guide clinicians in choosing a tailored treatment. Data from large studies investigating the role of immunotherapy in gastrointestinal cancers are promising but further investigations are necessary to better select those patients who can mostly benefit from these novel therapies. This review will focus on the treatment of metastatic esophageal and gastric cancer. We will review the standard of care and the role of novel therapies such as immunotherapies and CAR-T. Moreover, we will focus on the analysis of potential predictive biomarkers such as Modify as: Microsatellite Instability (MSI) and PD-L1, which may lead to treatment personalization and improved treatment outcomes. A multidisciplinary point of view is mandatory to generate an integrated approach to properly exploit these novel antiproliferative agents. [ABSTRACT FROM AUTHOR]

The failure of therapies directed at targets within cancer cells highlight the necessity for a paradigm change in cancer therapy. The attention of researchers has shifted towards the disruption of cancer cell interactions with the tumor microenvironment. A typical example of such a disruption is the immune checkpoint cancer therapy that disrupts interactions between the immune and the cancer cells. The interaction of cancer antigens with T cells occurs in the immunological synapses. This is characterized by several special features, i.e., the proximity of the immune cells and their target cells, strong intercellular adhesion, and secretion of signaling cytokines into the intercellular cleft. Earlier, we hypothesized that the cancer-associated fibroblasts interacting with cancer cells through a synapse-like adhesion might play an important role in cancer tumors. Studies of the interactions between cancer cells and cancer-associated fibroblasts showed that their clusterization on the membrane surface determined their strength and specificity. The hundreds of interacting pairs are involved in the binding that may indicate the formation of synapse-like structures. These interactions may be responsible for successful metastasis of cancer cells, and their identification and disruption may open new therapeutic possibilities. [ABSTRACT FROM AUTHOR]

The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to modulate DC functions for elevating the anti-tumor effects of DNA vaccines. Therefore, the influences of various inhibitors of mTOR (mTORi) on the expressions of DC maturation markers, the abilities of antigen presenting and processing of BMM-derived DCs and the tumor killing effects of E7-specific CD8+ T lymphocytes activated by BMM-derived DCs were in vitro examined. The anti-tumor effects of connective tissue growth factor (CTGF)/E7 DNA vaccine and/or mTORi were also in vivo analyzed. In our study, suppressive effects of mTORi on the DC maturation markers expressed on BMMCs could be reversed. The mTORi-treated mature BMM-derived DCs tended to be non-apoptotic. These mTORi-treated BMM-derived DCs could have better antigen presenting and processing abilities. The E7-specific cytotoxic CD8+ T lymphocytes could have more potent tumoricidal activity following activation of mTORi-treated BMM-derived DCs. For tumor-bearing mice, those treated with CTGF/E7 DNA vaccine and mTORi indeed can have higher percentages of mature DCs in the TME, better disease control and longer survivals. Consequently, application of mTORi can be a pharmacological approach for temporally increasing life span, antigen presenting and antigen processing of DCs to strengthen the therapeutic outcome of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Therapeutic blockade of PD-1/PD-L1 shows promising results in Hodgkin's lymphoma (HL) and in some diffuse large B-cell lymphoma (DLBCL) patients, but biomarkers predicting such responses are still lacking. To this end, we recently developed a transcriptional scoring of immune escape (IE) in cancer biopsies. Using this method in DLBCL, we identified four stages of IE correlated with overall survival, but whether Hodgkin's lymphomas (HL) also display this partition was unknown. Thus, we explored the transcriptomic profiles of ~1000 HL and DLBCL using a comparative meta-analysis of their bulk microarrays. Relative to DLBCL, the HL co-clustered at the advanced stage of immune escape, displaying significant enrichment of both IE and T-cell activation genes. Analyses via transcriptome deconvolution and immunohistochemistry showed more CD3+ and CD4+ tumor-infiltrating lymphocytes (TILs) in HL than DLBCL. Both HL and non-GCB DLBCL shared a high abundance of infiltrating CD8+ T-cells, but HL had less CD68+CD163+ macrophages. The same cellular distribution of PD-1 and TIM-3 was observed in HL and DLBCL, though HL had more PD-L1 tumor cells and LAG-3 ME cells. This study illuminates the advanced stage of immune activation and escape in HL, consistent with the response to checkpoint blockade therapies for this type of lymphoma. [ABSTRACT FROM AUTHOR]