Interferons in cancer immunoediting: sculpting metastasis and immunotherapy response

Abstract

Interferons (IFNs) are pleiotropic cytokines critical for regulation of epithelial cell functions and for immune system regulation. In cancer, IFNs contribute to tumor-intrinsic and -extrinsic mechanisms that determine the quality of antitumor immunity and response to immunotherapy. In this Review, we focus on the different types of tumor IFN sensitivity that determine dynamic tumor-immune interactions and their coevolution during cancer progression and metastasis. We extend the discussion to new evidence supporting immunotherapy-mediated immunoediting and the dual opposing roles of IFNs that lead to immune checkpoint blockade response or resistance. Understanding the intricate dynamic responses to IFN will lead to novel immunotherapeutic strategies to circumvent protumorigenic effects of IFN while exploiting IFN-mediated antitumor immunity.

Figure 1. Types of IFN insensitivity: primary and acquired.

Primary IFN insensitivity arises from mutations or epigenetic marks, leading to IFN-insensitive tumor cells. Acquired IFN insensitivity can be generated from tumors that initially respond to IFN but, as a result of clonal selection or phenotypic conversions, turn insensitive. Both types are driven and sustained by two forces of tumor evolution: tumor progression and immunoediting.

Figure 2. Tumor-extrinsic and -intrinsic effects of IFN during immunoediting.

Elimination phase: IFNs orchestrate the pace of elimination by controlling cell proliferation, differentiation, and senescence; and by increasing tumor immunogenicity, immune infiltration, and adaptive immunity attack to clear tumor cells. Equilibrium phase: Remaining tumor cells, which survive immune attack, are poorly sensitive to IFN and thus less immunogenic and less visible to the adaptive immune system. Senescent cells can persist at this stage, and other IFN-nonresponsive cells can acquire stem cell abilities, such as self-renewal, maintaining the survival of this cell population contributing to tumor survival. Overall, there is a dynamic equilibrium of cell cycling and death mediated by the crosstalk of tumor and innate and adaptive immunity. Escape phase: IFN-insensitive proliferative clones, which also express immunosuppressive ligands to evade adaptive immunity, burst out. Tumor-extrinsic effects of IFN are mediated mainly by dendritic cells and macrophages. An immunosuppressive microenvironment leads to the expression of immunosuppressive receptors in CD8⁺ T cells, reducing the immune attack. Immunotherapy: During immunotherapy, the immune pressure is accentuated, leading to further immunoediting. Acute IFN signaling increases tumor immunogenicity, which turns cancer cells vulnerable to immune attack, favoring immunotherapy response and tumor regression. On the other hand, immunoedited cells are poorly differentiated and highly aggressive. Chronic IFN signaling contributes to immunosuppression by the upregulation of multiple immunosuppressive ligands, causing resistance to ICB monotherapy.

Figure 3. IFN effects during metastasis.

Antimetastatic effects: IFNs might reduce tumor cell dissemination through upregulation of E-cadherin by IFN type I, thus inhibiting epithelial-mesenchymal transition (EMT). Also, CD8⁺ T cells and Th1 cells secrete IFN type II, which downregulates both CXCR4 and VEGF, suppressing dissemination and angiogenesis, respectively. Upon dissemination, EMT-like single circulating tumor cells (CTCs) are susceptible to NK cell–mediated killing, while CTC clusters contain epithelial-like cells that are less susceptible to NK cell–mediated cytotoxicity, causing reduced IFN-γ production by NK cells. At the metastatic site, tumors display reduced IRF7 expression, diminishing IFN and visibility to CD8⁺ T and NK cell immune attack. Prometastatic effects: Myeloid-derived suppressor cells (MDSCs) release IFN type III, which activates STAT3, engaging the EMT process. IFN types I and II are produced by tumor cells, driving the recruitment of immunosuppressive neutrophils that decrease immune attack during dissemination. Also, IFN types I and II lead to CCL2 secretion and increase recruitment of Tregs to the metastatic site, supporting the seeding of tumor cells. Genomic instability triggers cGAS/STING pathways, promoting invasion and metastasis. The dynamic interaction with immunity could be the cause of tumor heterogeneity loss and the increase in clonal tumor selection driven by IFN sensitivity. Immune hostile challenges accumulate throughout the process, contributing to immunoediting.