Muriel Moser

An important question is how chemotherapy may (re-)activate tumor-specific immunity. In this study, we provide a phenotypic, functional and genomic analysis of tumor-specific CD8⁺ T cells in tumor (P815)-bearing mice, treated or not with cyclophosphamide. Our data show that chemotherapy favors the development of effector-type lymphocytes in tumor bed, characterized by higher KLRG-1 expression, lower PD-1 expression and increased cytotoxicity. This suggests re-engagement of T lymphocytes into the effector program. IFN-I appears involved in this remodeling. Our findings provide some insight into how cyclophosphamide regulates the amplitude and quality of tumor-specific immune responses.

In theory, the immunotherapy of cancer should induce the selective destruction of cancer cells and a long-term specific protection, based on the specificity and memory of immunity. This contrasts with the collateral damages of conventional therapies and their toxic effects on host tissues. However, recent data suggest that chemotherapy may potentiate ongoing immune responses, through homeostatic mechanisms. Massive tumor death, empty “immune” niches and selected cytokines may act as a danger signal, alerting the immune system and amplifying pre-existing antitumor reactivity.

In the last decade, a growing body of evidence has highlighted the major role of cancer immunosurveillance. The immune system can recognize tumor cells and keep them under check for long period of time, but is impeded by escape mechanisms induced by the tumor itself. Interestingly, the efficacy of chemotherapy has been shown to depend on the immune response, which in turn is potentiated by chemical agents, creating a positive feedback loop leading to long term tumor resistance. In this review, we summarize some mechanisms underlying the synergy between chemo- and immuno-therapy.

The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) patients and in scurfy mice emphasize the critical role played by thymus‐derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here, we demonstrate that tTregs selectively inhibit CD27/CD70‐dependent Th1 priming, while leaving the IL‐12‐dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN‐γ‐secreting CD4+ T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27‐dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responses. See also: [L Wojciech & L Ignatowicz][1] (May 2015) ![][2] Regulatory T cells (Tregs) control inflammatory responses by inhibiting the CD70‐dependent pathway of Th1 priming while sparing IL‐12 production. By decreasing CD70 cell surface expression on DCs, Tregs enhance the threshold of activation of Th1‐type responses, thereby restraining potentially harmful inflammatory responses. The EMBO Journal (2015) 34: 1336–1348 [1]: http://dx.doi.org/10.15252/embj.201591547 [2]: pending:yes

The classical view of the Th1/Th2 paradigm posits that the pathogen nature, infectious cycle and persistence represent key parameters controlling the choice of effector mechanisms operating during an immune response. Thus, efficient Th1 responses are triggered by replicating intracellular pathogens, while Th2 responses would control helminth infection and promote tissue repair during the resolution phase of an infectious event. However, this vision does not account for a growing body of data describing how pathogens exploit the polarization of the host immune response to their own benefit. Recently, the study of macrophages has illustrated a novel aspect of this arm race between pathogens and the immune system, and the central role of macrophages in homeostasis, repair and defense of all tissues is now fully appreciated. Like T lymphocytes, macrophages differentiate into distinct effectors including classically (M1) and alternatively (M2) activated macrophages. Interestingly in addition to represent immune effectors, M1/M2 cells have been shown to represent potential reservoir cells to a wide range of intracellular pathogens. Subversion of macrophage cell metabolism by microbes appears as a recently uncovered immune escape strategy. Upon infection, several microbial agents have been shown to activate host metabolic pathways leading to the production of nutrients necessary to their long term persistence in host. The purpose of this review is to summarize and discuss the strategies employed by pathogens to manipulate macrophage differentiation, and in particular their basic cell metabolism, to favor their own growth while avoiding immune control.

The transcription factor hypoxia inducible factors (HIF)‐1 functions as a master regulator of oxygen homeostasis. There is increasing evidence that HIF has an essential role to prevent tissue damage in physiological and pathological situations in which cells are deprived of O₂. Here, we review the effects of decreased oxygen supply on the innate and adaptive immune responses in the gut and in solid tumors in which the oxygenation profile correlates with the grade of inflammation. Data in the literature indicate that some tumors may co‐opt immune mechanisms induced by HIF‐1 to promote their survival and proliferation. By contrast, HIF‐1 stabilization would have a beneficial effect in the intestinal tract as it would dampen inflammation and promote its resolution. Therefore, stabilization of HIF‐1 in hypoxia may have opposite effects on the integrity of the host, depending on the tissue microenvironment.

It was recently proposed that T lymphocytes, which closely interact with APCs, can extract surface molecules from the presenting cells when they dissociate. These observations question the classical view of discrete interactions between phenotypically defined cell populations. In this review, we summarize some reports suggesting that membrane exchange at the immune synapse can be a vector for intercellular communication and envisage some consequences on the biology of T cells.

There is increasing evidence that the effect of chemotherapy on tumor growth is not cell autonomous but relies on the immune system. The objective of this study was therefore to decipher the cellular and molecular mechanisms underlying the role of innate and adaptive immunity in chemotherapy‐induced tumor rejection. Treatment of DBA/2 mice bearing P815 mastocytoma with cyclophosphamide induced rejection and long‐term protection in a CD4‐ and CD8‐dependent manner. A population of inflammatory‐type dendritic cells was dramatically expanded in the lymph nodes of mice that rejected the tumor and correlated with CD4‐dependent infiltration, in tumor bed, of tumor‐specific CD8⁺ T lymphocytes. Our data point to a major role of CD4⁺ T cells in inducing chemokine expression in the tumor, provoking migration of tumor‐specific CXCR3⁺ CD8⁺ T lymphocytes. Importantly, the analysis of CD8⁺ T cells specific to P1A/H‐2L^d and P1E/H‐2K^d revealed that cyclophosphamide altered the P815‐specific CD8 T repertoire by amplifying the response specific to the mutated P1E antigen.

The majority of rodent and human tumors express antigens that can be recognized by T lymphocytes and are infiltrated by immune cells. Although tumor infiltration by T lymphocytes has been associated with a favorable prognosis, the role of dendritic cells (DCs), which may present tumor-associated antigens in an immunogenic or tolerogenic context, remains elusive. Here, we discuss recent observations suggesting that the function of DCs in the tumor microenvironment may impact the spontaneous resistance of neoplasms to chemotherapy as well as treatment outcome.