Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer

Abstract

Immune checkpoint inhibitors (ICIs) in the form of anti-CTLA-4 and anti-PD-1/PD-L1 have become the frontier of cancer treatment and successfully prolonged the survival of patients with advanced non-small cell lung cancer (NSCLC). But the efficacy varies among different patient population, and many patients succumb to disease progression after an initial response to ICIs. Current research highlights the heterogeneity of resistance mechanisms and the critical role of tumor microenvironment (TME) in ICIs resistance. In this review, we discussed the mechanisms of ICIs resistance in NSCLC, and proposed strategies to overcome resistance.

Keywords: immunotherapy; lung cancer; mechanism; resistance; tumor microenvironment.

Figure 1

Immune checkpoint inhibitor therapy. Immune response to cancer and relationship among cancer cells, T cells and antigen presenting cells. (A) Tumor cells are recognized by the intrinsic immune cells. Once recognized, immune cells trigger initial intrinsic immunity and IFN secretion, promoting chemokines production, and the recruitment of immune cells. Mature DCs take up tumor antigens, which finally presented as MHC-I antigenic tumor peptides complex, migrate to the draining lymph nodes, where initial tumor-specific Th1 CD4⁺ T cells and CTLs are induced by antigen cross-presentation. IL-2 and IL-15 help to maintain CTLs production and viability. (B) Mechanism of anti-PD-1/PD-L1/CTLA-4 antibody. PD-1 is expressed on T cells, while PD-L1 is expressed on tumor cells. These two form the PD-1/PD-L1 axis that mediates T cell function inhibition. The function of anti-PD-1/PD-L1 antibodies lies in restoring the T cell effect by blocking the PD-1/PD-L1 interaction. CTLA-4 on T cells binds to B7 ligand on the APC, leading to immunosuppression. Anti-CTLA-4 antibodies inhibit the binding between CTLA-4 and B7, which prolongs T cell activation, restore T cell proliferation, and establish an immune response to tumor-associated antigens. IFN, interferon; DC, dendritic cell; MHC-I, major histocompatibility complex class I; CTL, cytotoxic T lymphocyte; APC, antigen-presenting cell.

Figure 2

Mechanisms of immune-mediated resistance to ICIs. (A) Lack of PD-L1, (B) Neoantigen-depletion, (C) Antigen presentation defect, (D) Tumor-mediated immune-suppression or –exclusion, (E) Immune inhibitory receptors, (F) Abnormal IFN signaling pathway, (G) Immunosuppressive cells, (H) Metabolic reprogramming, (I) The ‘3Es’ hypothesis. IFN, interferon; ICIs, immune checkpoint inhibitor.