IFN-γ orchestrates tumor elimination, tumor dormancy, tumor escape, and progression

Abstract

Tumor immunoediting consisting of three phases of elimination, equilibrium or dormancy, and escape has been supported by preclinical and clinical data. A comprehensive understanding of the molecular mechanisms by which antitumor immune responses regulate these three phases are important for developing highly tailored immunotherapeutics that can control cancer. To this end, IFN-γ produced by Th1 cells, cytotoxic T cells, NK cells, and NKT cells is a pleiotropic cytokine that is involved in all three phases of tumor immunoediting, as well as during inflammation-mediated tumorigenesis processes. This essay presents a review of literature and suggests that overcoming tumor escape is feasible by driving tumor cells into a state of quiescent but not indolent dormancy in order for IFN-γ-producing tumor-specific T cells to prevent tumor relapse.

Interferon gamma in cancer immunotherapy

“…For immune cells, IFNγ signaling activates antigen‐presenting cells (APCs) to upregulate the expressions of cytokines (IL‐12 and IL‐18) and costimulatory molecule CD86 that enhance Th1 differentiation and cytotoxic T lymphocyte (CTL) function . Furthermore, those APCs activated by IFNγ increase the expression of MHC molecules and components of the antigen‐processing machinery.…”

“…For immune cells, IFNγ signaling activates antigenpresenting cells (APCs) to upregulate the expressions of cytokines (IL-12 and IL-18) and costimulatory molecule CD86 that enhance Th1 differentiation and cytotoxic T lymphocyte (CTL) function. [26][27][28] Furthermore, those APCs activated by IFNγ increase the expression of MHC molecules and components of the antigen-processing machinery. In addition, IFNγ induces a number of signals in T cells to enable T cell function effectively, while the loss of IFNγ signaling pathways in T cells dampens T cell responses and allows tumor growth and persistence.…”

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer

“…Immunotherapeutics that target disseminated cancer dormancy may aid to control or eliminate cancer state. In this view, treatment modalities that induce or amplify the CTL immune response or abrogate CTL immunosuppression mediated by cancer cells might be beneficial to confine or eradicate metastatic cells [112]. Meanwhile, an association of human Tregs, neutrophils and inflammatory mediators such as interferon-gamma (IFNγ) are rather context-dependent [109].…”

“…Immunotherapeutics that target disseminated cancer dormancy may aid to control or eliminate cancer state. In this view, treatment modalities that induce or amplify the CTL immune response or abrogate CTL immunosuppression mediated by cancer cells might be beneficial to confine or eradicate metastatic cells [112]. Dormancy state induced by the elimination of primary tumor can be avoided by a "recombinant T cell receptor ligand therapy", dosing days in advance to tumor resection and lasting throughout the whole treatment course, that is a highly speculative therapy [113].…”

Enhancement of Oncolytic Activity of oHSV Expressing IL-12 and Anti PD-1 Antibody by Concurrent Administration of Exosomes Carrying CTLA-4 miRNA

“…Production of IFNs is a hallmark of immunotherapeutic antitumor activity [35,36]. In the studies reported here we measured the production of IFN-γ in mice implanted with A20 tumor cells and injected with 1 × 107 pfu of T1012G, T2850, or T3855 oHSV.…”