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PD-1 blockade rescues failing anticancer immune responses, resulting in durable remissions in some cancer patients. Cytokines such as IFNγ and IL-2 contribute to the anti-tumor effect of PD-1 blockade. IL-9 was identified over the last decade as a cytokine demonstrating a potent ability to harness the anticancer functions of innate and adaptive immune cells in mice. Recent translational investigations suggest that the anticancer activity of IL-9 also extends to some human cancers. Increased T cell-derived IL-9 was proposed to predict the response to anti-PD-1 therapy. Preclinical investigations accordingly revealed that IL-9 could synergize with anti-PD-1 therapy in eliciting anticancer responses. Here, we review the findings suggesting an important contribution of IL-9 in the efficacy of anti-PD-1 therapy and discuss their clinical relevance. We will also discuss the role of host factors like the microbiota and TGFβ in the tumor microenvironment (TME) in the regulation of IL-9 secretion and anti-PD-1 treatment efficacy. [ABSTRACT FROM AUTHOR]

Endogenous danger signals are molecules normally present in a given cell compartment that are rapidly released following cell stress and induce immune responses. We and others have shown that dying tumor cells treated with some chemotherapies are able to induce anticancer immune responses, which rely on their release of danger signals such as the nuclear protein HMGB1. DNA can also be released from chemotherapy-treated tumor cells, act as a danger signal, and boost anticancer immunity. While the immunostimulatory properties of DNA have been identified for decades, the recent discovery of a novel family of receptors, cytosolic DNA sensors, has provided a novel impetus not only to understand how chemotherapy can trigger anticancer immune responses but also to exploit DNA-derived molecules for therapeutic use. We will here discuss the molecular characteristics of endogenous danger signals released from chemotherapy-treated tumor cells and focus on the clinical relevance of using these danger signals in chemoimmunotherapeutic strategies against cancer. [ABSTRACT FROM AUTHOR]

CD4 T cells are key components of the immune system that shape the anticancer immune response in animal models and in humans. The biology of CD4 T cells is complex because naïve T cells can differentiate into various subpopulations with various functions. Recently, a new population called Th9 cells was described. These cells are characterized by their ability to produce IL9 and IL21. They were first described in the context of parasite infections and allergic processes. However, some reports described their presence in the tumor bed in mice and humans. Their high secretion of IL9 and IL21 in the tumor bed contributes to their anticancer functions. Indeed, these cytokines trigger the activation of dendritic cells, mast cells, natural killer cells, and CD8 T cells to mount an antitumor immune response, thus explaining the remarkable ability of Th9 cells to control tumor growth. This review summarizes the latest advances in the Th9 field in cancer and focuses on their potential role as new tool for cell therapy. [ABSTRACT FROM AUTHOR]

IL-9-producing T cells can harbour potent anti-cancer functions. In this issue of the British Journal of Cancer, Almeida et al. found that the host microbiota enhances in vivo T cell-derived secretion of IL-9, thereby limiting cancer outgrowth. [ABSTRACT FROM AUTHOR]

The immune system has important roles in limiting the spread of cancer and shaping the tumor microenvironment. Although the contributions of T helper 17 (Th17) cells (a subtype of CD4+ T lymphocytes) to autoimmunity and allergy response are well known, their roles in cancer remain ambiguous. Despite adoptive transfer studies indicating that mouse Th17 cells support anticancer immunity, the Th17 cells that naturally infiltrate experimental tumors appear to have a tumor-promoting effect. These contradictory properties can be related to the high degree of plasticity inherent in Th17 cells and their capacity to differentiate into tumoricidal Th1-like cells. Mouse Th17 cells induced by transforming growth factor-β (TGF-β) express CD39 and CD73 ectonucleotidases on their surfaces, which leads to adenosine release and suppression of T cell immunity. Here, we discuss how TGF-β acts as a molecular switch controlling the immunoregulatory properties of Th17 cells. [Copyright &y& Elsevier]

Abstract: Accumulating evidence indicates that IL-27, a member of the IL-12 family of cytokines, alleviates the severity of autoimmune diseases in both mice and men. The IL-27-induced activation of signal transducer and activator of transcription (Stat)1 and Stat3 promotes the generation of IL-10- producing type 1 regulatory T (Tr1) cells that inhibit effector T cells. In addition, IL-27 also suppresses the development of pathogenic IL-17-producing CD4+ T cells (TH17) cells suggesting that pharmacological manipulations of IL-27 signaling pathway could be exploited therapeutically in regulating tissue inflammation. Here, we review how IL-27 controls inflammation through the regulation of Tr1 and TH17 responses. [Copyright &y& Elsevier]

Abstract: The ability of IL-10 producing Type 1 regulatory T cells (Tr1) to restrain the activation of effector immune cells during autoimmune responses underscores their essential role in maintaining immune tolerance. While mouse studies have demonstrated that increasing the numbers and/or function of Tr1 cells could improve the course of autoimmune diseases, the inability to generate Tr1 cells in vitro in large numbers has hampered identification of the molecular mechanisms responsible for their differentiation. Interleukin-27 (IL-27), a member of the IL-12 heterodimeric cytokine family, was identified as an important cytokine that suppresses effector TH17 cells and promotes the generation of Tr1 cells. Tr1 cells dampen autoimmunity and tissue inflammation partly through their secretion of the immunosuppressive cytokine IL-10. Here we review the molecular mechanisms involved in IL-27-induced Tr1 cell differentiation, with a focus on the role of two transcription factors, the aryl hydrocarbon receptor (AhR) and c-Maf. We also discuss how ligands that bind to AhR and affect the biology of IL-27-induced Tr1 cells can be exploited as a therapeutic approach to alleviate human autoimmune diseases. [Copyright &y& Elsevier]

Abstract: Dendritic cells (DCs) are central to the initiation of tumor-specific immune responses. However, the tumor microenvironment generates immunosuppressive cells and soluble mediators that compromise DC functions and limit the success of DC-based therapies. Progress in understanding DC metabolism in cancer is uncovering novel therapeutic targets that could restore DC capacity to prime T cells and trigger effective anticancer responses. Accumulating evidence also indicates that conventional chemo- and radiotherapy protocols can cause DC activation, enhance antigen cross-presentation, selectively eliminate immunosuppressive cells and revert the immunosuppression state caused by cancer, suggesting that relevant chemoimmunotherapy associations could fully exploit DC capacity to trigger anticancer responses. Here, we discuss recent strategies that harness DC against cancer. [Copyright &y& Elsevier]

Type 1 regulatory T cells (Tr1 cells ) that produce interleukin 10 (IL-10) are instrumental in the prevention of tissue inflammation, autoimmunity and graft-versus-host disease. The transcription factor c-Maf is essential for the induction of IL-10 by Tr1 cells, but the molecular mechanisms that lead to the development of these cells remain unclear. Here we show that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which was induced by IL-27, acted in synergy with c-Maf to promote the development of Tr1 cells. After T cell activation under Tr1-skewing conditions, the AhR bound to c-Maf and promoted transactivation of the Il10 and Il21 promoters, which resulted in the generation of Tr1 cells and the amelioration of experimental autoimmune encephalomyelitis. Manipulating AhR signaling could therefore be beneficial in the resolution of excessive inflammatory responses. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-γ (IFN-γ)–producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X7 purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1β (IL-1β). The priming of IFN-γ–producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3−/−) or caspase-1–deficient (Casp-1−/−) mice unless exogenous IL-1β is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7−/− or Nlrp3−/− or Casp1−/− hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells. [ABSTRACT FROM AUTHOR]

Tumors that progress do so via their ability to escape the antitumor immune response through several mechanisms, including developing ways to induce the differentiation and/or recruitment of CD4+CD25+ Tregs. The Tregs, in turn, inhibit the cytotoxic function of T cells and NK cells, but whether they have an effect on the cytotoxic function of tumor-infiltrating DCs (TIDCs) has not been determined. Here we have shown, in 2 rodent models of colon cancer, that CD4+CD25+ Tregs inhibit the ability of CD11b+ TIDCs to mediate TNF-related apoptosis-inducing ligand-induced (TRAIL-induced) tumor cell death. In both models of cancer, combination treatment with Mycobacterium bovis Bacillus Calmette-Guérin (BCG), which activates the innate immune system via TLR2, TLR4, and TLR9, and cyclophosphamide (CTX), which depletes Tregs, eradicated the tumors. Further analysis revealed that the treatment led to a marked increase in the number of CD11b+ TIDCs that killed the tumor cells via a TRAIL-dependent mechanism. Furthermore, acquisition of TRAIL expression by the CD11b+ TIDCs was induced by BCG and dependent on signaling through TLR2, TLR4, and TLR9. In vivo transfer of Tregs abrogated the ability of BCG to induce CD11b+ TIDCs to express TRAIL and thereby nullified the efficacy of the CTX-BCG treatment. Our data have therefore delineated what we believe to be a novel mechanism by which Tregs inhibit the antitumor immune response. [ABSTRACT FROM AUTHOR]

Physiological cell death, which occurs as a continuous byproduct of cellular turnover, is non-immunogenic or even tolerogenic, thereby avoiding autoimmunity. By contrast, cancer cell death elicited by radiotherapy and some chemotherapeutic agents such as anthracyclines is immunogenic. Recent data suggest that innate and cognate immune responses elicited by such anti-cancer agents are required for an optimal therapeutic outcome, underscoring the clinical relevance of immunogenic cell death. Here we discuss the concept that immunogenic death involves changes in the composition of the cell surface, as well as the release of soluble immunogenic signals that occur in a defined temporal sequence. This ‘key’ then operates on a series of receptors expressed by dendritic cells (DC, the ‘lock’) to allow for the presentation of tumor antigens to T cells and for the initiation of a productive immune response. Immunogenic cell death is characterized by the early cell surface exposure of chaperones including calreticulin and/or heat shock proteins, which determine the uptake of tumor antigens and/or affect DC maturation. Moreover, the late release of High mobility group box 1 (HMGB1), which acts on toll-like receptor 4 (TLR4), is required for optimal presentation of antigens from dying tumor cells. Nonetheless, numerous details on the molecular events that define immunogenicity remain to be defined, both at the level of the dying cancer cells and at the level of the responding innate effectors. [Copyright &y& Elsevier]

Although the impact of tumor immunology on the clinical management of most cancers is still negligible, there is increasing evidence that anticancer immune responses may contribute to the control of cancer after conventional chemotherapy. Thus, radiotherapy and some chemotherapeutic agents, in particular anthracyclines, can induce specific immune responses that result either in immunogenic cancer cell death or in immunostimulatory side effects. This anticancer immune response then helps to eliminate residual cancer cells (those that fail to be killed by chemotherapy) or maintains micrometastases in a stage of dormancy. Based on these premises, in this Review we address the question, How may it be possible to ameliorate conventional therapies by stimulating the anticancer immune response? Moreover, we discuss the rationale of clinical trials to evaluate and eventually increase the contribution of antitumor immune responses to the therapeutic management of neoplasia. [ABSTRACT FROM AUTHOR]

The current method of cancer management takes into account tumor-related factors to predict therapeutic outcome. However, recent evidence indicates that the host immune system also contributes to therapeutic outcome. Here, we highlight anthracyclines, which have been used to treat a broad range of cancers since the 1960s, as an example of an anticancer treatment that can boost the host''s immune system to improve the efficacy of chemotherapy. It has recently been revealed that the translocation of calreticulin to the plasma membrane in tumor cells and the release of high-mobility-group box 1 (HMGB1) by tumor cells are two key post-transcriptional events required for the immunogenicity of anthracyclines. These discoveries represent a conceptual advance in the understanding of the mechanisms underlying the immunogenicity of anthracyclines. We review the effects of anthracyclines on the host immune system and discuss how this knowledge can be exploited for anticancer therapy. [Copyright &y& Elsevier]

Accumulating evidence indicates that the innate and adaptive immune systems make a crucial contribution to the antitumour effects of conventional chemotherapy-based and radiotherapy-based cancer treatments. Moreover, the molecular and cellular bases of the immunogenicity of cell death that is induced by cytotoxic agents are being progressively unravelled, challenging the guidelines that currently govern the development of anticancer drugs. Here, we review the immunological aspects of conventional cancer treatments and propose that future successes in the fight against cancer will rely on the development and clinical application of combined chemo- and immunotherapies. [ABSTRACT FROM AUTHOR]

For the last four decades, the treatment of cancer has relied on four treatment modalities, namely surgery, radiotherapy, cytotoxic chemotherapy, and hormonotherapy. Most of these therapies are believed to directly attack and eradicate tumor cells. The emerging concept that cancer is not just a disease of a tissue or an organ but also a host disease relies on evidence of tumor-induced immunosuppression and polymorphisms in genes involved in host protection against tumors. This theory is now gaining new impetus, based on our recent data showing that optimal therapeutic effects require the immunoadjuvant effect of tumor cell death induced by cytotoxic anticancer agents. Here, we show that the release of the high mobility group box 1 protein (HMGB1) by dying tumor cells is mandatory to license host dendritic cells (DCs) to process and present tumor antigens. HMGB1 interacts with Toll-like receptor 4 (TLR4) on DCs, which are selectively involved in the cross-priming of anti-tumor T lymphocytes in vivo. A TLR4 polymorphism that affects the binding of HMGB1 to TLR4 predicts early relapse after anthracycline-based chemotherapy in breast cancer patients. This knowledge may be clinically exploited to predict the immunogenicity and hence the efficacy of chemotherapeutic regimens. [ABSTRACT FROM AUTHOR]

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen–specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death. [ABSTRACT FROM AUTHOR]

Cancer results from a tumor cell intrinsic dysregulation of oncogenes, tumor suppressor and stability genes as well as from the avoidance of immunosurveillance. A complex network of cellular interactions allows one to mount cognate anti-tumor immune responses. Recently, discoveries have been made regarding the links between innate and cognate antitumor immunity eliciting protective T-cell responses. The intricate differentiation pathway, whereby dendritic cells can efficiently mature in the tumor microenvironment, appears crucial for the priming of T cells. Transformed cells might deliver danger signals directly to the dendritic cell. Alternatively, other cell types belonging to the innate immune system can sense transformed cells through a specific set of receptors and then interact with dendritic cells to modulate their activation state. A novel subset of innate effector cells called interferon-producing killer dendritic cells are multitasking chimeras that can recognize and kill transformed cells, and undergo a maturation state of antigen presentation. Also, evidence has been produced suggesting that cell death promoted by conventional chemotherapy or radiotherapy might elicit interactions between the innate and the cognate immune system that result in anti-tumor immune responses. [Copyright &y& Elsevier]

[Display omitted] • T H 9 mediate potent anticancer functions against melanoma upon adoptive transfer. • IL-9 and IL-21 mediate T H 9 cell anticancer functions. • Co-signalling receptor targeting can harness T H 9 cell anticancer functions. • PD-1 signalling restrains T H 9 cell effector functions. • Circulating T H 9 cell frequency may predict anti-PD-1 therapy efficacy in humans. CD4 T cell effector subsets not only profoundly affect cancer progression, but recent evidence also underscores their critical contribution to the anticancer efficacy of immune checkpoint inhibitors. In 2012, the two seminal studies suggested the superior antimelanoma activity of T H 9 cells over other T cell subsets upon adoptive T cell transfer. While these findings provided great impetus to investigate further the unique functions of T H 9 cells and explore their relevance in cancer immunotherapy, the following questions still remain outstanding: are T H 9 cell anticancer functions restricted to melanoma? What are the factors favouring T H 9 cell effector functions? What is the contribution of T H 9 cells to cancer immunotherapy treatments? Can T H 9 cells be identified in humans and, if so, what is their clinical relevance? By reviewing the studies addressing these questions, we will discuss how T H 9 cells could be therapeutically harnessed for cancer immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Whereas preclinical investigations and clinical studies have established that CD8+T cells can profoundly affect cancer progression, the underlying mechanisms are still elusive. Challenging the prevalent view that the beneficial effect of CD8+T cells in cancer is solely attributable to their cytotoxic activity, several reports have indicated that the ability of CD8+T cells to promote tumor regression is dependent on their cytokine secretion profile and their ability to self-renew. Evidence has also shown that the tumor microenvironment can disarm CD8+T cell immunity, leading to the emergence of dysfunctional CD8+T cells. The existence of different types of CD8+T cells in cancer calls for a more precise definition of the CD8+T cell immune phenotypes in cancer and the abandonment of the generic terms “pro-tumor” and “antitumor.” Based on recent studies investigating the functions of CD8+T cells in cancer, we here propose some guidelines to precisely define the functional states of CD8+T cells in cancer. [ABSTRACT FROM PUBLISHER]

The efficacy of checkpoint inhibitor therapy illustrates that cancer immunotherapy, which aims to foster the host immune response against cancer to achieve durable anticancer responses, can be successfully implemented in a routine clinical practice. However, a substantial proportion of patients does not benefit from this treatment, underscoring the need to identify alternative strategies to defeat cancer. Despite the demonstration in the 1990's that the detection of danger signals, including the nucleic acids DNA and RNA, by dendritic cells (DCs) in a cancer setting is essential for eliciting host defence, the molecular sensors responsible for recognising these danger signals and eliciting anticancer immune responses remain incompletely characterised, possibly explaining the disappointing results obtained so far upon the clinical implementation of DC-based cancer vaccines. In 2008, STING (stimulator of interferon genes), was identified as a protein that is indispensable for the recognition of cytosolic DNA. The central role of STING in controlling anticancer immune responses was exemplified by observations that spontaneous and radiation-induced adaptive anticancer immunity was reduced in the absence of STING, illustrating the potential of STING-targeting for cancer immunotherapy. Here, we will discuss the relevance of manipulating the STING signalling pathway for cancer treatment and integrating STING-targeting based strategies into combinatorial therapies to obtain long-lasting anticancer immune responses. [ABSTRACT FROM AUTHOR]

Background: Inflammasomes are large protein complexes that assemble in the cytosol in response to danger such as tissue damage or infection. Following activation, inflammasomes trigger cell death and the release of biologically active forms of pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18. NOD‐like receptor family pyrin domain containing 6 (NLRP6) inflammasome is required for IL‐18 secretion by intestinal epithelial cells, macrophages, and T cells, contributing to homeostasis and self‐defense against pathogenic microbes. However, the involvement of NLRP6 in type 2 lung inflammation remains elusive. Methods: Wild‐type (WT) and Nlrp6−/− mice were used. Birch pollen extract (BPE)‐induced allergic lung inflammation, eosinophil recruitment, Th2‐related cytokine and chemokine production, airway hyperresponsiveness, and lung histopathology, Th2 cell differentiation, GATA3, and Th2 cytokines expression, were determined. Nippostrongylus brasiliensis (Nb) infection, worm count in intestine, type 2 innate lymphoid cell (ILC2), and Th2 cells in lungs were evaluated. Results: We demonstrate in Nlrp6−/− mice that a mixed Th2/Th17 immune responses prevailed following birch pollen challenge with increased eosinophils, ILC2, Th2, and Th17 cell induction and reduced IL‐18 production. Nippostrongylus brasiliensis infected Nlrp6−/− mice featured enhanced early expulsion of the parasite due to enhanced type 2 immune responses compared to WT hosts. In vitro, NLRP6 repressed Th2 polarization, as shown by increased Th2 cytokines and higher expression of the transcription factor GATA3 in the absence of NLRP6. Exogenous IL‐18 administration partially reduced the enhanced airways inflammation in Nlrp6−/− mice. Conclusions: In summary, our data identify NLRP6 as a negative regulator of type 2 immune responses. [ABSTRACT FROM AUTHOR]

Treatment of metastatic cancer mainly relies on chemotherapy. Chemotherapeutic agents kill tumor cells by direct cytotoxicity, thus leading to tumor regression. However, emerging data focus on another side of cancer chemotherapy: its antitumor immunity effect. Although cancer chemotherapy was usually considered as immunosuppressive, some chemotherapeutic agents have recently been shown to activate an anticancer immune response, which is involved in the curative effect of these treatments. Cancer development often leads to the occurrence of an immune tolerance that prevents cancer rejection by the immune system and hinders efficacy of immunotherapy. Cancer cells induce proliferation and local accumulation of immunosuppressive cells such as regulatory T cells and immature myeloid cells, and prevent the maturation of dendritic cells and their capacity to present tumor antigens to T lymphocytes. Many anticancer cytotoxic agents interfere with the molecular and cellular mechanisms leading to tumor-induced tolerance. They can restore an efficient immune response that contributes to the therapeutic effects of chemotherapy. These findings open a novel field of investigations for future clinical trial design, taking into account the immunostimulatory capacity of chemotherapeutic agents, and using them in combined chemo-immunotherapy strategies when tumor-induced tolerance is overcome. [ABSTRACT FROM AUTHOR]

Impressive remissions driven by immunological checkpoint blockade in cancer patients have prompted the scientific community to investigate afresh the crosstalk between cancer cells and the patient's immune system. Preclinical and clinical studies have highlighted that the anticancer efficacy of some conventional chemotherapeutics is based on their ability to restore anticancer immune responses. The current challenge is to understand and circumvent immune resistance mechanisms to chemo- and immunotherapies to design relevant immunotherapy and chemotherapy combinations. In this review, we will summarize which immunological processes are involved in the anticancer action of some cytotoxic agents and discuss the recently unraveled contribution of the gut microbiota into the immunogenicity of anticancer drugs. We will eventually introduce the scientific rationale for therapeutic strategies combining chemotherapeutic drugs and immune checkpoint blockers. [ABSTRACT FROM AUTHOR]

Dietary polyphenols, derived from natural products, have received a great interest for their chemopreventive properties against cancer. In this study, we investigated the effects of phenolic extract of the oleaster leaves (PEOL) on tumor growth in mouse model and on cell death in colon cancer cell lines. We assessed the effect of oleaster leaf infusion on HCT116 (human colon cancer cell line) xenograft growth in athymic nude mice. We observed that oleaster leaf polyphenol-rich infusion limited HCT116 tumor growth in vivo. Investigations of PEOL on two human CRC cell lines showed that PEOL induced apoptosis in HCT116 and HCT8 cells. We demonstrated an activation of caspase-3, -7 and -9 by PEOL and that pre-treatment with the pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), prevented PEOL-induced cell death. We observed an involvement of the mitochondrial pathway in PEOL-induced apoptosis evidenced by reactive oxygen species (ROS) production, a decrease of mitochondrial membrane potential, and cytochrome c release. Increase in intracellular Ca2+ concentration induced by PEOL represents the early event involved in mitochondrial dysfunction, ROS-induced endoplasmic reticulum (ER) stress and apoptosis induced by PEOL, as ruthenium red, an inhibitor of mitochondrial calcium uptake inhibited apoptotic effect of PEOL, BAPTA/AM inhibited PEOL-induced ROS generation and finally, N-acetyl-L-cysteine reversed ER stress and apoptotic effect of PEOL. These results demonstrate that polyphenols from oleaster leaves might have a strong potential as chemopreventive agent in colorectal cancer. [ABSTRACT FROM AUTHOR]

IL-9 was initially identified as a T cell growth factor with a potential oncogenic activity. Accordingly, IL-9 drives tumor growth in most hematological cancers. However, the links between IL-9 and cancer progression have been recently revisited following the discovery of T9 cells. T9 cells, which have been characterized in 2008 as a proinflammatory CD4 T cell subset that promotes protection against parasites and drives tissue inflammation in colitis, actually harbor potent IL-9-dependent anti-cancer properties in solid tumors and especially melanoma. While the molecular mechanisms underlying these observations are still being investigated, T9 cells were demonstrated to activate both innate and adaptive immune responses, thereby favoring anti-cancer immunity and tumor elimination. Human T9 cells have also been identified in cancer tissues, but their functions remain elusive. The present review aims to discuss the anti-cancer potential of T9 cells and their possible clinical relevance for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Summary The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-γ-producing γδT cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable “oncomicrobiotics” ameliorating the efficacy of the most common alkylating immunomodulatory compound. [ABSTRACT FROM AUTHOR]

Cytotoxic anticancer drugs can promote antitumor immune responses. The anticancer activity of 5-fluorouracil (5FU) relies on the restoration of T-cell immunity following the elimination of myeloid-derived suppressor cells (MDSCs). We have recently discovered that the 5FU-driven activation of the NLRP3 inflammasome in MDSCs promotes tumor angiogenesis by eliciting TH17 responses that compromise anticancer immunity. This underscores the need to combine 5-FU with NLRP3 inhibitors to prevent tumor progression. [ABSTRACT FROM AUTHOR]

Aims: Impairment in adenosine monophosphate-activated protein kinase (AMPK) activity and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation are associated with several metabolic and inflammatory diseases. In this study, we investigated the role of AMPK/NLRP3 inflammasome axis in the molecular mechanism underlying pain perception. Results: Impairment in AMPK activation induced by compound C or sunitinib, two AMPK inhibitors, provoked hyperalgesia in mice ( p<0.001) associated with marked NLRP3 inflammasome protein activation and increased serum levels of interleukin-1β (IL-1β) (24.56±0.82 pg/ml) and IL-18 (23.83±1.882 pg/ml) compared with vehicle groups (IL-1β: 8.15±0.44; IL-18: 4.92±0.4). This effect was rescued by increasing AMPK phosphorylation via metformin treatment ( p<0.001), caloric restriction diet ( p<0.001), or NLRP3 inflammasome genetic inactivation using NLRP3 knockout (nlrp3−/−) mice ( p<0.001). Deficient AMPK activation and overactivation of NLRP3 inflammasome axis were also observed in blood cells from patients with fibromyalgia (FM), a prevalent human chronic pain disease. In addition, metformin treatment (200 mg/daily), which increased AMPK activation, restored all biochemical alterations examined by us in blood cells and significantly improved clinical symptoms, such as, pain, fatigue, depression, disturbed sleep, and tender points, in patients with FM. Innovation and Conclusions: These data suggest that AMPK/NLRP3 inflammasome axis participates in chronic pain and that NLRP3 inflammasome inhibition by AMPK modulation may be a novel therapeutic target to fight against chronic pain and inflammatory diseases as FM. Antioxid. Redox Signal. 24, 157-170. [ABSTRACT FROM AUTHOR]

The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4+ T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation. [ABSTRACT FROM AUTHOR]

The TH9 subset of helper T cells was initially shown to contribute to the induction of autoimmune and allergic diseases, but subsequent evidence has suggested that these cells also exert antitumor activities. However, the molecular events that account for their effector properties are elusive. Here we found that the transcription factor IRF1 enhanced the effector function of TH9 cells and dictated their anticancer properties. Under TH9-skewing conditions, interleukin 1β (IL-1β) induced phosphorylation of the transcription factor STAT1 and subsequent expression of IRF1, which bound to the promoters of Il9 and Il21 and enhanced secretion of the cytokines IL-9 and IL-21 from TH9 cells. Furthermore, IL-1β-induced TH9 cells exerted potent anticancer functions in an IRF1- and IL-21-dependent manner. Our findings thus identify IRF1 as a target for controlling the function of TH9 cells. [ABSTRACT FROM AUTHOR]

Background: The importance of immune responses in the control of melanoma growth is well known. However, the implication of these antitumor immune responses in the efficacy of dacarbazine, a cytotoxic drug classically used in the treatment of melanoma, remains poorly understood in humans. Methods: In this prospective observational study, we performed an immunomonitoring of eleven metastatic or locally advanced patients treated with dacarbazine as a first line of treatment. We assessed by flow cytometry lymphoid populations and their activation state; we also isolated NK cells to perform in vitro cytotoxicity tests. Results: We found that chemotherapy induces lymphopenia and that a significantly higher numbers of naïve CD4+ T cells and lower proportion of Treg before chemotherapy are associated with disease control after dacarbazine treatment. Interestingly, NK cell cytotoxicity against dacarbazine-pretreated melanoma cells is only observed in NK cells from patients who achieved disease control. Conclusion: Together, our data pinpoint that some immune factors could help to predict the response of melanoma patients to dacarbazine. Future larger scale studies are warranted to test their validity as prediction markers. [ABSTRACT FROM AUTHOR]

Significance: Accumulating evidence indicates that the success of some anticancer treatments (select chemotherapies or radiotherapy or trastuzumab) could be related to the stimulation of an anticancer immune response through the induction of an immunogenic tumor cell death (ICD). Recent Advances: Preclinical data revealed that dying tumor cells can emit a series of danger signals (so-called 'cell-death-associated molecular patterns' (CDAMP)) that will dictate the recruitment and activation of specific inflammatory phagocytes. Hence, tumor cells succumbing to ICD are characterized by specific metabolic and molecular changes that will trigger a hierarchy of polarizing cytokine-producing cells, culminating in the recruitment and reactivation of antitumor interferon-γ-producing effector T cells which contribute to the success of cytotoxic treatments. Critical Issues: In this review, we summarize the molecular and cellular bases of this ICD, underscoring the crucial role of high mobility group box 1 protein (HMGB1) and adenosine tri-phosphate, both of which are released from dying tumor cells during ICD and are implicated in the chemotherapy-elicited anticancer immune response. Future Directions: We discuss here how such CDAMP could serve as predictive biomarkers that could discriminate immunogenic from nonimmunogenic anti-cancer compounds, and, in case of deficiency, could be compensated by surrogate products to ameliorate the success rate of conventional anticancer treatment modalities. Antioxid. Redox Signal. 20, 1098-1116. [ABSTRACT FROM AUTHOR]

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pTH17) cells and memory TH1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pTH17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pTH17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response. [ABSTRACT FROM AUTHOR]

Activation of the transcription factor PPARg by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARγ are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory T-helper (TH)17 cells. Accordingly, TH17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPARγ by DHA. Furthermore, naïve CD4 T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into TH17 cells. In two different mouse models of cancer, DHA prevented tumor outgrowth and angiogenesis in an IL-17-dependent manner. Altogether, our results uncover a novel molecular pathway by which PPARγ-induced SOCS3 expression prevents IL-17-mediated cancer growth. [ABSTRACT FROM AUTHOR]

Bleomycin (BLM) is an anticancer drug currently used for the treatment of testis cancer and Hodgkin lymphoma. This drug triggers cancer cell death via its capacity to generate radical oxygen species (ROS). However, the putative contribution of anticancer immune responses to the efficacy of BLM has not been evaluated. We make here the observation that BLM induces immunogenic cell death. In particular, BLM is able to induce ROS-mediated reticulum stress and autophagy, which result in the surface exposure of chaperones, including calreticulin and ERp57, and liberation of HMBG1 and ATP. BLM induces anti-tumor immunity which relies on calreticulin, CD8+ T cells and interferon-γ. We also find that, in addition to its capacity to trigger immunogenic cell death, BLM induces expansion of Foxp3+ regulatory T (Treg) cells via its capacity to induce transforming growth factor beta (TGFβ) secretion by tumor cells. Accordingly, Treg cells or TGFβ depletion dramatically potentiates the antitumor effect of BLM. We conclude that BLM induces both anti-tumor CD8+ T cell response and a counteracting Treg proliferation. In the future, TGFβ or Treg inhibition during BLM treatment could greatly enhance BLM anti-tumor efficacy. [ABSTRACT FROM AUTHOR]

Dacarbazine (DTIC) is a cytotoxic drug widely used for melanoma treatment. However, the putative contribution of anticancer immune responses in the efficacy of DTIC has not been evaluated. By testing how DTIC affects host immune responses to cancer in a mouse model of melanoma, we unexpectedly found that both natural killer (NK) and CD8+ T cells were indispensable for DTIC therapeutic effect. Although DTIC did not directly affect immune cells, it triggered the upregulation of NKG2D ligands on tumor cells, leading to NK cell activation and IFNγ secretion in mice and humans. NK cell-derived IFNγ subsequently favored upregulation of major histocompatibility complex class I molecules on tumor cells, rendering them sensitive to cytotoxic CD8+ T cells. Accordingly, DTIC markedly enhanced cytotoxic T lymphocyte antigen 4 inhibition efficacy in vivo in an NK-dependent manner. These results underscore the immunogenic properties of DTIC and provide a rationale to combine DTIC with immunotherapeutic agents that relieve immunosuppression in vivo. [ABSTRACT FROM AUTHOR]

Chemotherapeutic agents are widely used for cancer treatment. In addition to their direct cytotoxic effects, these agents harness the host's immune system, which contributes to their antitumor activity. Here we show that two clinically used chemotherapeutic agents, gemcitabine (Gem) and 5-fluorouracil (5FU), activate the NOD-like receptor family, pyrin domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1? (IL-1?), which curtails anticancer immunity. Chemotherapy-triggered IL-1? secretion relied on lysosomal permeabilization and the release of cathepsin B, which bound to Nlrp3 and drove caspase-1 activation. MDSC-derived IL-1? induced secretion of IL-17 by CD4+ T cells, which blunted the anticancer efficacy of the chemotherapy. Accordingly, Gem and 5FU exerted higher antitumor effects when tumors were established in Nlrp3?/? or Casp1?/? mice or wild-type mice treated with interleukin-1 receptor antagonist (IL-1Ra). Altogether, these results identify how activation of the Nlrp3 inflammasome in MDSCs by 5FU and Gem limits the antitumor efficacy of these chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Summary: Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4+ and CD8+ T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer. [Copyright &y& Elsevier]

The concept of immunogenic chemotherapy that has recently emerged relies upon the capacity of a cytotoxic compound to trigger a cell-death modality. This modality elicits cross-priming by dendritic cells of tumor antigen-specific T cells that will contribute to the tumoricidal activity of the compound and protect the host against relapse. In contrast, most anticancer drugs elicit nonimmunogenic apoptosis that is not accompanied with an immunizing property. This review will discuss some molecular and metabolic changes required at the level of the tumor that must engage key pathways at the level of the host for the induction of Tc1 polarized-protective T cell responses during chemotherapy. We will summarize the immune adjuvants that can boost the immunogenicity of cell death to augment the efficacy of chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: An attractive, yet hitherto unproven concept predicts that the promotion of tumor regression should elicit the host''s immune response against residual tumor cells to achieve an optimal therapeutic effect. In a way, chemo- or radiotherapy must trigger “danger signals” emitted from immunogenic cell death and hence elicit “danger associated molecular patterns” to stimulate powerful anticancer immune responses. Here, based on the recent experimental and clinical evidence, we will discuss the molecular identity of the multiple checkpoints that dictate the success of “immunogenic chemotherapy” at the levels of the drug, of the tumor cell and of the host immune system. [Copyright &y& Elsevier]

Conventional cancer treatments mediate their effects via the direct elimination of tumor cells. Nonetheless, recent evidence indicates that radiotherapy and some chemotherapeutic agents can also induce specific immune responses that contribute to therapeutic outcomes. Two major tumor-intrinsic changes that determine the immune response against tumors have been identified: the translocation of calreticulin to the plasma membrane and the release of high-mobility group box 1 protein. Together, these changes improve engulfment and processing of apoptotic bodies by dendritic cells, which are involved in the cross-priming of antitumor T lymphocytes in vivo. We review these two molecular mechanisms that dictate the radio/chemotherapy-elicited antitumor immune response and discuss how this knowledge can be clinically exploited to predict and also ameliorate the success of chemo/radiotherapy. [ABSTRACT FROM AUTHOR]

The conventional treatment of cancer relies upon radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Nonetheless, there are circumstances in which conventional anti-cancer therapy can induce a modality of cellular demise that elicits innate and cognate immune responses, which in turn mediate part of the anti-tumor effect. Although different chemotherapeutic agents may kill tumor cells through an apparently homogeneous apoptotic pathway, they differ in their capacity to stimulate immunogenic cell death. We discovered that the pre-apoptotic translocation of intracellular calreticulin (endo-CRT) to the plasma membrane surface (ecto-CRT) is critical for the recognition and engulfment of dying tumor cells by dendritic cells. Thus, anthracyclines and γ-irradiation that induce ecto-CRT cause immunogenic cell death, while other pro-apoptotic agents (such as mitomycin C and etoposide) induce neither ecto-CRT nor immunogenic cell death. Depletion of CRT abolishes the immunogenicity of cell death elicited by anthracyclines, while exogenous supply of CRT or enforcement of CRT exposure by pharmacological agents that favor CRT translocation can enhance the immunogenicity of cell death. For optimal anti-tumor vaccination and immunogenic chemotherapy, the same cells have to expose ecto-CRT and to succumb to apoptosis; if these events affect different cells, no anti-tumor immune response is elicited. These results may have far reaching implications for tumor immunology because (i) ecto-CRT exposure by tumor cells allows for the prediction of therapeutic outcome and because (ii) the re-establishment of ecto-CRT may ameliorate the efficacy of chemotherapy. [ABSTRACT FROM AUTHOR]

The treatment of cancer by chemotherapy causes tumour cell death, mostly by apoptosis. This tumour cell death may or may not elicit an immune response. At least in some cases, the efficacy of chemotherapy critically depends on the induction of immunogenic cell death that is a type of cell demise that stimulates the activation of an adaptative anti-tumour immune response, which in turn helps to eradicate residual cancer (stem) cells. Indeed, anthracyclins care more efficient in curing tumours in immunocompetent than in T cell-deficient mice. The molecular mechanism implicated in this anti-tumour T cell activation was recently discovered. Anthracyclins cause immunogenic cell death due to their specific capacity to stimulate the translocation of calreticulin to the cell surface. Calreticulin then acts as an “eat me” signal for dendritic cells, allowing them to phagocytose tumour cells and to prime tumour antigen-specific cytotoxic T cells. Importantly, non-immunogenic chemotherapy can be rendered immunogenic by adsorbing recombinant calreticulin to tumour cells or by enforcing the translocation of endogenous calreticulin to the cell surface by means of PP1/GADD34 inhibitors. This strategy could have major implications for the treatment of human cancer. Indeed, in vivo treatments with anthracyclins can cause the translocation of calreticulin to the surface of circulating tumour cells, in patients with acute myeloid leukaemia (AML). The challenge will be to determine whether the exposure of calreticulin translocation on the tumour cell surface is linked to chemotherapy-induced anti-tumour immune responses and therapeutic efficacy in human cancer. [ABSTRACT FROM AUTHOR]

Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy. [ABSTRACT FROM AUTHOR]

The interferon (IFN)-γ–induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice. Here we show that the main source of IFN-γ is not the conventional NK cell but a subset of B220+Ly6C− dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220+NK1.1+ dendritic cells secrete high levels of IFN-γ and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2−/−Il2rg−/− mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response. [ABSTRACT FROM AUTHOR]