The Resistance Mechanisms of Lung Cancer Immunotherapy

Abstract

Immunotherapy has revolutionized lung cancer treatment in the past decade. By reactivating the host's immune system, immunotherapy significantly prolongs survival in some advanced lung cancer patients. However, resistance to immunotherapy is frequent, which manifests as a lack of initial response or clinical benefit to therapy (primary resistance) or tumor progression after the initial period of response (acquired resistance). Overcoming immunotherapy resistance is challenging owing to the complex and dynamic interplay among malignant cells and the defense system. This review aims to discuss the mechanisms that drive immunotherapy resistance and the innovative strategies implemented to overcome it in lung cancer.

Keywords: Immune check inhibitor; PD-1/PD-L1; immunotherapy; lung cance; resistance mechanism.

FIGURE 1

Mechanisms of resistance to immunotherapy. (A) Tumor intrinsic mechanisms that are associated with resistance to immunotherapy include lack of tumor immunogenicity (low TMB, heterogenous antigens, mutation of certain genes, and IPRES transcriptional signatures), deficiency in antigen presentation (alterations in INF-γ signaling pathway, HLA LOH, B2M, and TAP deletion), aberrations in several signaling pathways (MAPK, PI3K, WNT, and IFN), and absent PD-L1 expression. (B) Host-related characteristics that lead to primary or secondary resistance include the gut microbiome, diet, concomitant medications, inflammation state, and autoimmunity. (C) Tumor extrinsic mechanisms involved in resistance to immunotherapy include T cell-related factors (alternative immune checkpoints, T cell exhaustion and phenotype alteration, TCR repertoire, and epigenetic modification), immunosuppressive cells (Treg, MDSC, and M2-TAM), and cytokines and metabolites (e.g., TGF-β, adenosine) released into the tumor microenvironment. Factors in the solid text boxes are involved in primary resistance, whereas those in the dotted text boxes are involved in secondary or acquired resistance. Factors with solid and dotted dual text boxes are involved in both. Cytokines with “+” and “-” represent positive and negative modulators to antitumor immune response, respectively. Abbreviations: TME, tumor microenvironment; MHC, major histocompatibility complex; TCR, T cell receptor; Treg, regulatory T cell; MDSC, myeloid-derived suppressor cell; M2-TAM, type II tumor-associated macrophage; ICR, immune checkpoint receptor; CAF, cancer-associated fibroblast; and IPRES, innate anti-PD-1 resistance.