Immunotherapy resistance in non-small-cell lung cancer: From mechanism to clinical strategies

Abstract

The high primary resistance incidence and unavoidable secondary resistance are the major clinical obstacle to lasting long-term benefits in Non-small-cell lung cancer (NSCLC) patients treated with immunotherapy. The mechanisms of immunotherapy resistance in NSCLC are complex, mainly involving tumor cells and tumor microenvironment (TME) infiltrating immune cells, including TAMs, B cells, NK cells, and T cells. The selection of clinical strategies for NSCLC progression after immunotherapy resistance should depend on the progressive mode. The progression pattern of NSCLC patients after immunotherapy resistance can be divided into oligo-progression and systemic/multiple progression, which should be considered for further treatment selection. In the future, it needs to explore how to optimize the combined therapy and explore strategies to reprogram infiltrating immune cells under various genetic backgrounds of tumor cells and timely reshape TME during antitumor treatments.

Keywords: NSCLC; TME; clinical strategies; immune cells; immunotherapy.

Figure 1

The incidence of primary resistance to immunotherapy in NSCLC patients. The highest incidence of primary resistance to ICIs was found in patients treated with ICIs as second-line treatment after chemotherapy failure, while the lowest incidence was found in NSCLC patients previously treated with immunotherapy plus chemotherapy.

Figure 2

The incidence of secondary resistance to immunotherapy in NSCLC patients. ICIs applied as first- and second-line treatment in treating NSCLC patients resulted in 52%-57% and 32%-64% rates of secondary resistance, respectively. MSKCC found that 78% of patients who acquired an initial response to PD-1 inhibitors further developed secondary resistance.

Figure 3

The definition and explanation of primary resistance and secondary resistance. Primary resistance: tumors in primary resistance NSCLC patients may contain no or only a few sensitive tumor cells to immunotherapy, which may present no active immune response (PD) or activate antitumor immune response followed by swiftly submerging by intricated mechanism (SD<6 months). Secondary resistance: When tumors contain no or only a few resistive tumor cells to immunotherapy, NSCLC patients will show a favorable and lasting response (CR, PR, SD) to immunotherapy (>6 months). However, some will form secondary resistance when tumor cells lose active response to immunotherapy by complicated mechanisms.

Figure 4

The mechanisms involved in immunotherapy resistance of NSCLC. Deficiency in tumor immunogenicity: various drive gene mutations affect PD-L1 expression, TMB, and tumor-specific neoantigen formation; Impaired antigen presentation: HLA loss, B2M mutation, IFN-γ signaling dysregulation, and some genes disorder; Abnormal signaling pathway: abnormal MAPK, PI3K, WNT, and IFN signaling pathways may influence tumor immunogenicity and antigen presentation; Abnormal activity and infiltration of immune cells in NSCLC TME: NSCLC TME enriched with increased M2 macrophages, decreased B cells, and NK cells form an immunosuppressive TME to resist the initiation of antitumor immunity. Some gene expression disorders or mutations in NSCLC cells can impair the activity, tumor-cell-killing function, proliferation, and infiltration of CD8+ T-cells in TME, which contribute to exhausted CD8+ T-cells for immunotherapy resistance.

Figure 5

The current clinical strategies and future perspectives in NSCLC patients after immunotherapy resistance. The selection of clinical treatment for NSCLC progression after immunotherapy resistance should be dependent on the progressive mode. Further studies can pay attention to optimizing the combined therapy and exploring strategies to modulate infiltrating immune cells and timely reshape TME.