Mechanisms of Cancer Resistance to Immunotherapy.

Rilan Bai,Jiuwei Cui,Naifei Chen,Lingyu Li,Zheng Lv,Huimin Tian,Nawen Du,Ling Bai

doi:10.3389/fonc.2020.01290

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.

Highlights

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
Several hypotheses for the development of HPD during immunotherapy were proposed by Champiat et al [5] For example, blockade of immune checkpoints (i) has the potential to functionally stimulate regulatory T cells (Tregs), locally creating an immunosuppressive microenvironment, that is, enhanced compensation of negative regulatory signals further aggravates T-cell depletion; (ii) has the potential to lead to polarization of immunosuppressive cells, such as M2 macrophages, dendritic cells (DCs), or myelocytes, producing immunosuppressive cytokines; and (iii) has the potential to stimulate TH1- and TH17-mediated inflammatory responses or lead to activation of certain driver gene pathways to activate oncogenic pathways, creating conditions for accelerated tumor growth and resistance to immunotherapy
Loss of function of adenosine deaminase acting on RNA (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 doublestranded RNA (dsRNA) ligand. This leads to tumor inflammation and growth inhibition, respectively, and profoundly sensitizes tumors to immunotherapy, overcoming resistance to immune checkpoint inhibitors (ICIs) [43]