Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

Abstract

Interferon-gamma (IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-γ in tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limited success. In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However, the IFN-γ-mediated responses are still positively associated with patient’s survival in several cancers. Consequently, major research efforts are required to understand the immune contexture in which IFN-γ induces its intricate and highly regulated effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways.

C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma

“…Thus, although intracellular C5aR1 expression by human T cells has been reported (53), our findings with PMX53 suggest the effects of C5aR1 signaling on murine T-cell populations are most likely indirect through the regulation of cytokines such as IFN-g. Produced predominantly by activated lymphocytes such as T h 1, CD8 + T, and NK cells, IFN-g is critical for both T-cell trafficking into tumors and cytotoxic functions of effector T cells (54). Consistent with the higher percentages of CD4 + T-cell subsets (55), plasma IFN-g levels were significantly increased in the absence of C5aR1 signaling (54).…”

“…Produced predominantly by activated lymphocytes such as T h 1, CD8 + T, and NK cells, IFN-g is critical for both T-cell trafficking into tumors and cytotoxic functions of effector T cells (54). Consistent with the higher percentages of CD4 + T-cell subsets (55), plasma IFN-g levels were significantly increased in the absence of C5aR1 signaling (54).…”

γδ T cells in cancer: a small population of lymphocytes with big implications

“…47 Interestingly, in vivo studies of skin cancer performed in cd Tcell-deficient mice (TCRd À/À mice) did not allow for discrimination between DETCs and other populations of cd T cells, and might have underestimated the role of dermal Vc4 + cd T cells or other subsets infiltrating the skin. 50 Interestingly, IFN-c production by cd T cells also enhances MHC I molecule expression at the surface of B16 melanoma cells, thereby promoting their recognition by CTLs ( Figure 2). 45,48,49 Importantly, a protective role for cd T cells in antitumor response in mice has been described in other models of cancer and notably in a spontaneous model of Bcell lymphoma.…”

“…49 macrophages and enhances the antigen presentation capacities of professional APCs. 50 Interestingly, IFN-c production by cd T cells also enhances MHC I molecule expression at the surface of B16 melanoma cells, thereby promoting their recognition by CTLs ( Figure 2). 51 A recent study in a mouse model of gastrointestinal stromal tumor describes a protective role for cd T cells mediated through the secretion of GM-CSF.…”

Evolution of chimeric antigen receptor (CAR) T cell therapy: current status and future perspectives

“…Since then, researchers have developed various therapeutic approaches for treating cancer through activation of the patient's immune system that are based on more solid biological rationales. Although early immunotherapeutic strategies, such as interleukin (IL)-2 and interferon (IFN)-c therapy, failed to produce meaningful clinical outcomes, the robust clinical responses to novel immunotherapies developed in the 2000s have begun to establish cancer immunotherapy as one of the major pillars of anticancer therapy (Lesterhuis et al 2011;Jiang et al 2016;Castro et al 2018). The therapeutic agents currently at the forefront of such clinical successes can be divided into three classes: immune checkpoint-blocking antibodies, T cell-recruiting bispecific antibodies, and chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) (Batlevi et al 2016).…”