Mechanisms of Cancer Resistance to Immunotherapy

Abstract

Over the last decade, based on the extensive development of preclinical animal studies and clinical trials, the efficacy, and mechanisms of immunotherapy have been fully explored. Significant and lasting clinical responses with immunotherapy provide a new breakthrough treatment for a variety of refractory cancer histologies, which gradually change the treatment pattern of tumors. However, although immune checkpoint inhibitor drugs are promising for achieving longer-term efficacy, their benefits in the overall population are still very low, such as low frequency of response in some common tumor types such as breast and prostate, and heterogeneity in the degree of response among different tumor lesions in the same patient, making immunotherapy with many limitations and challenges. Most patients do not respond to immunotherapy or inevitably develop resistance to treatment after a period of treatment, manifesting with primary resistance or acquired resistance who initially respond to treatment. The mechanisms of tumor immune resistance are very complex and involve multiple aspects such as genes, metabolism, inflammation, and abnormal neovascularization. Currently, many mechanisms of immunotherapy resistance have been characterized, and more continue to be uncovered. These efforts can improve the quality of medical care for cancer diagnosis and treatment, which improve the quality of life of patients, and finally lead to accurate individualized treatment. This review discusses mechanisms of cancer immunotherapy resistance including tumor-intrinsic factors and tumor-extrinsic factors.

Keywords: IFN-γ; immunotherapy; mechanism; neoplasm; resistance.

Figure 1

Mechanisms of cancer resistance to immunotherapy. Key mechanisms of cancer resistance to immunotherapy are briefly described in the figure, including: (I) Tumor-intrinsic factors: (i) alteration of antitumor immune response pathways: (1) aberrant expression of tumor antigens and changes in immunogenicity (e.g., TAA, TSA, antigenic drift, ER stress and autophagy, genes involved in mitochondrial metabolism); (2) alterations in the antigen presentation pathways [e.g., proteasome, transporters, MHC (loss of HLA expression, β2-M mutations leading to loss of HLA)]; (ii) alteration of signaling pathways (e.g., interferon γ and its associated-signaling pathway); (iii) forming immunosuppressive microenvironment: (1) secreting inhibitory molecules (e.g., exosome PD-L1, PD-L1 variant fragment); (2) functional gene mutations [e.g., Wnt/β-catenin signaling, PTEN/PI3K (phosphatase and tensin homolog/phosphatidylinositol 3-kinase) signaling, CDK4-CDK6 signaling, MAPK signaling, EGFR, KRAS, STK11, PAK4]; (3) altering metabolism in TME [e.g., hypoxic, expression of IDO, LXR, CD38/adenosine, CD73]; (II) factors of tumor local microenvironment: (i) immunosuppressive cells/molecules: immunosuppressive cells [e.g., MDSCs, Tregs, TAM]; activation of coinhibitory receptors (e.g., PD-L1, CTLA-4, TIM-3, TIGHT); inhibition of costimulatory receptor (e.g., CD28); (ii) abnormal neovascularization; (III) host-related factors: (i) gender; (ii) age; (iii) distribution of body fat; (iv) gut microbiome.

Figure 2

Interferon γ signaling pathway. IFN-γ signaling pathway: IFN-γ → IFNγR1/2 → JAK1/2 → STAT1/2 → IRF1 → genes encoding MHC-I or PD-L1 promoter; activating mutations in tyrosine–protein phosphatase non-receptor type 2 (Ptpn2) negatively regulates JAK1 and STAT1 signaling; loss of function of PBAF complex unique genes (Pbrm1, Arid2, and Brd7) increased chromatin reachability to transcription regulator elements of IFN-γ-inducible genes within tumor cells and subsequently increased production of CXCL9/CXCL10 chemokines, leading to more efficient recruitment of T_effs to tumor tissue; loss of function of the RNA-editing enzyme ADAR1 in tumor cells could reduce A-to-I editing of IFN-inducible RNA species and elicit a sensing response of melanoma differentiation-associated protein 5 (MDA5) and PKR to dsRNA ligand, which leads to tumor inflammation and growth inhibition, respectively.