Acquired Resistance to PD-1/PD-L1 Blockade in Lung Cancer: Mechanisms and Patterns of Failure

Abstract

Immunotherapy is now the preferred treatment for most lung cancer patients. It is used to treat unresectable stage III non-small-cell lung cancer and is the first-line therapy for non-oncogene-driven advanced/metastatic non-small-cell lung cancer patients (either alone or in combination with chemotherapy). Unfortunately, most patients that respond initially to immunotherapy develop resistance over time, thus limiting the durability of immunotherapy. A better understanding of the mechanisms of acquired resistance is urgently needed to expand the benefit of immunotherapy in lung cancer patients. This review aims to summarize the mechanisms and clinical outcomes of acquired resistance of anti-PD-1/PD-L1 therapies in non-small-cell lung cancer patients.

Non-Small Cell Lung Cancer: Challenge and Improvement of Immune Drug Resistance

“…Just as the PACIFIC trial evaluated the efficacy of durvalumab consolidation therapy in patients with NSCLC after simultaneous RT and chemotherapy, the results showed that the mPFS was 16.9 vs. 5.6 months (HR: 0.55, 95% CI: 0.45-0.68), and the mOS was 47.5 vs. 28.1 months (HR: 0.55, 95% CI: 0.45-0.68) (41). In addition, a retrospective study at the 2020 ASCO conference showed that local treatment can significantly improve survival benefits (42). After immune resistance, local therapy combined with immunotherapy can reverse drug resistance to some extent, providing new treatment ideas for patients with immune drug resistance.…”

Innovative immunotherapy targeting at PD-1/PD-L1 signaling pathway: mechanism, efficacy and safety analysis of monotherapy and combination therapies in non-small cell lung cancer (NSCLC) treatment

“…PD-1 and PD-L1 foster the immunosuppressive microenvironment, invalidate immunological surveillance, and help tumor cells escape from T cells via various pathways [14][15]. Different from CTLA-4, PD-1/PD-L1 pathway expresses its inhibitory function in a more indirect way.…”

“…Since the recognition of antigenic peptides is necessary for effective T cell-mediated response to ICIs, the loss of antigen and MHA molecules presentation leads to acquired resistance to ICIs [14]. Scientists have identified that immunoediting can trigger the development of tumor clones with low MHC (major histocompatibility complex) expression or poor bind between neoantigens and MHC during tumorigenesis [14,21,22]. PD-1 blockade can reinvigorate exhausted CD8 + T cells (Tex), restoring their anti-tumor effector functionality [23].…”

“…When CD8 + T cells are infiltrated in the TME, it can increase dysfunction driven by chromatin remodeling and epigenetic modifications and eventually reach a state of fixed epigenetic dysfunction in which their chromatin is rendered inaccessible and is thus resistant to further remodeling and reinvigoration by anti-PD-1 therapy. Therefore, a lack of memory T cells and reexhausted CD8 + T cells might lead to acquired resistance to PD-1 blockade [14,24,25].…”

“…Besides IFN-γ signaling, expression of other immune checkpoint molecules, including CTLA-4, T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and V-domain Ig suppressor of T cell activation (VISTA), etc. has been proposed to lead to acquired resistance to PD-1/PD-L1 blockade [14,27].…”