Cancer immunotherapy with immune checkpoint inhibitors (ICIs): potential, mechanisms of resistance, and strategies for reinvigorating T cell responsiveness when resistance is acquired

Abstract

Cancer is still the leading cause of death globally. The approval of the therapeutic use of monoclonal antibodies against immune checkpoint molecules, notably those that target the proteins PD-1 and PD-L1, has changed the landscape of cancer treatment. In particular, first-line PD-1/PD-L1 inhibitor drugs are increasingly common for the treatment of metastatic cancer, significantly prolonging patient survival. Despite the benefits brought by immune checkpoint inhibitors (ICIs)-based therapy, the majority of patients had their diseases worsen following a promising initial response. To increase the effectiveness of ICIs and advance our understanding of the mechanisms causing cancer resistance, it is crucial to find new, effective, and tolerable combination treatments. In this article, we addressed the potential of ICIs for the treatment of solid tumors and offer some insight into the molecular pathways behind therapeutic resistance to ICIs. We also discuss cutting-edge therapeutic methods for reactivating T-cell responsiveness after resistance has been established.

Keywords: Acquired resistance; Breast cancer; Glioblastoma; Immune checkpoint inhibitor (ICIs); Immunotherapy; Melanoma; Non-small cell lung cancer; Prostate cancer; Renal cell carcinoma.

Fig. 1

Immune Checkpoint Inhibitor against Tumor Cell. Through the interaction between PD-1 expressed on the surface of T cells and PD-L1 expressed on the surface of tumor cells, the immunological checkpoint prevents T-cell activation. Through contact between PD-1 on the surface of T cells and anti-PD-1 antibodies, T cell activation and immunological attack are enabled

Fig. 2

The interaction between the TCR and the tumor-specific antigen shown in the context of MHC II results in T cell activation. Following the activation of a number of downstream targets that PD-1 releases in response to interaction with either of its ligands, programmed cell death-ligand 1 (PD-L1) or 2 (PD-L2), deactivation of T cells takes place, which ultimately leads to the suppression of cytotoxic T lymphocytes (CTL). While controlling CTL activity may work as a brake to lower the likelihood of autoimmunity against host antigens, inhibiting CTL activation will be employed by forming tumor cells to evade the host's immune surveillance, which will lead to the growth of the tumor. The interaction of ICIs mAbs to PD-1, PD-L1, PD-L2, and CTLA4 restores T cell activation and slows the growth of tumors

Fig. 3

Blockade of CTLA-4 or PD-1 Signaling in Tumor Immunotherapy. Dendritic cells (DC) and naive T cells interact in the lymph node during the priming phase. The interaction between the TCR and the tumor-associated antigen shown in the context of MHC II constitutes the activation signals. The interaction between CD28 and B7 expressed on the surface of DC is one of the additional activation signals. The immune system attacks and eliminates tumor cells as a result of the effector phase, which takes place in the peripheral tissue. At this stage, PD-1 and PD-L1 inhibitory signals on T cells are suppressed, effectively activating T cells against the tumor antigen

Fig. 4

Combination Treatment of Pancreatic Cancer. In PDAC, the autophagy cargo receptor NBR1 directs an autophagy-dependent pathway that targets MHC-I molecules for lysosomal degradation. MHC-I is more frequently identified inside autophagosomes and lysosomes than on the cell surfaces of PDAC cells. Notably, restoring surface levels of MHC-I in syngeneic host mice results in improved antigen presentation, increased anti-tumor T cell responses, and inhibition of tumor growth. To enhance the anti-tumor immune response, dual ICI therapy (anti-PD1 and anti-CTLA4 antibodies) is used in conjunction with autophagy suppression, either genetically or pharmacologically with chloroquine