IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting

Abstract

Genetic evolution that occurs during cancer progression enables tumour heterogeneity, thereby fostering tumour adaptation, therapeutic resistance and metastatic potential. Immune responses are known to select (immunoedit) tumour cells displaying immunoevasive properties. Here we address the role of IFN-γ in mediating the immunoediting process. We observe that, in several mouse tumour models such as HA-expressing 4T1 mammary carcinoma cells, OVA-expressing EG7 lymphoma cells and CMS5 MCA-induced fibrosarcoma cells naturally expressing mutated extracellular signal-regulated kinase (ERK) antigen, the action of antigen-specific cytotoxic T cell (CTL) in vivo results in the emergence of resistant cancer cell clones only in the presence of IFN-γ within the tumour microenvironment. Moreover, we show that exposure of tumours to IFN-γ-producing antigen-specific CTLs in vivo results in copy-number alterations (CNAs) associated with DNA damage response and modulation of DNA editing/repair gene expression. These results suggest that enhanced genetic instability might be one of the mechanisms by which CTLs and IFN-γ immunoedits tumours, altering their immune resistance as a result of genetic evolution.

Cancer immune escape: MHC expression in primary tumours versus metastases

“…15 It was recently reported that that interferon (IFN) released by tumourinfiltrating lymphocytes can induce DNA damage and mutations, promoting the MHC/HLA class I heterogeneity observed in primary tumours. 16 These data suggest that tumour-infiltrating lymphocytes per se may possibly promote the Generation of Diversity in the primary tumour and that the genetic instability observed in some tumours may not be the main driving force inducing MHC/HLA changes.…”

“…We have defined two different stages of this process: a ‘permissive phase’, when T lymphocytes are infiltrating the tumour niche and killing cancer cells; and an ‘encapsulated phase’, when the tumour is composed solely of MHC class I‐negative cells and T lymphocytes are retained only in the surrounding stroma of a granuloma‐like structure . It was recently reported that that interferon (IFN) released by tumour‐infiltrating lymphocytes can induce DNA damage and mutations, promoting the MHC/HLA class I heterogeneity observed in primary tumours . These data suggest that tumour‐infiltrating lymphocytes per se may possibly promote the Generation of Diversity in the primary tumour and that the genetic instability observed in some tumours may not be the main driving force inducing MHC/HLA changes.…”

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

“…Thirdly, they produce TNF-related apoptosis-inducing ligand (TRAIL) to engage with TRAIL receptors on tumor cells and in turn induce tumor cell apoptosis [3]. Finally, activated lymphocytes produce IFN- γ , which is a pleiotropic cytokine with a wide range of activity; IFN- γ simultaneously induces apoptosis, tumor dormancy, and immunoediting in tumor cells that could lead to tumor relapse and progression [4–8]. Paradoxically, chronic exposure of cells to IFN- γ facilitates the development of hepatocellular carcinoma [9], colorectal carcinoma [10], and papilloma [11].…”

“…In addition to apoptosis inducing and tumor inhibitory functions, IFN- γ can also induce aberrant DNA methylation [29, 30] or genetic alteration in tumor cells [4], resulting in tumor progression and relapse. IFN- γ -induced tumor immunoediting is mediated through several mechanisms which include the induction of tumor antigen loss [30–34], upregulation of PD-L1 in tumor cells [35], recruitment of myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) to the tumor site [36, 37].…”

“…In addition, chronic IFN- γ signaling in tumor cells increases resistance to immune checkpoint blockade through STAT1-related epigenetic and transcriptomic alterations, rendering melanoma resistant to radiation therapy and immune checkpoint inhibitors [39]. It was suggested that the genomic instability induced by IFN- γ during tumor progression is due to adaptation of the tumor to an immunologically hostile microenvironment [4]. This phenomenon has been predicted by the adaptation model of immunity [40, 41].…”