Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Abstract

Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

Keywords: Cancer immunotherapy; Immune cells; Immune checkpoint blockade; PD-1/PD-L1; Precision medicine.

Fig. 1

Summary of biomarkers of the response to anti-PD-1/PD-L1 immunotherapy. The efficacy of PD-1/PD-L1 blockade therapy is mainly predicted by PD-1/PD-L1 expression, microsatellite instability, tumor mutation load, and bone marrow-derived suppressor cells. The roles and significance of POLE, TGF-β, TGF-β, NLR, ANC, IDO1, and various chemokines are summarized. Biomarkers are shown in red

Fig. 2

Anti-PD-1/PD-L1 immunotherapy resistance caused by antigen recognition disorders. Loss of heterozygosity and frameshift mutations in beta-2-microglobulin (B2M) disrupt tumor antigen presentation, and PD-1-positive T cell infiltration is associated with B2M. MHCII promotes CD4+ T cell infiltration and expresses the inhibitory receptor LAG3, which limits antigen presentation and causes primary resistance to PD-1 blockade therapy

Fig. 3

Inhibiting T cell activity causes anti-PD-1/PD-L1 immunotherapy resistance. After PD-1 blockade, the secretion of cytokines, including TNF and IF-36, causes T cell gene alterations, which inhibits cytotoxicity, promotes TIM-3 and VISTA inhibitory checkpoint expression, up-regulates CD38, and promotes ATRA secretion and binding to adenosine receptor and adenosine inhibition of T cell activation. The deletion of PTEN in tumors activates the PI3K/AKT pathway through multiple routes, including phosphorylation of Akt and activation of S6K1, to promote PD-L1 expression and inhibit T cell activation

Fig. 4

Reduced T cell infiltration leads to drug resistance. The secretion of IL-6, G-CSF, and CXCL1 promotes the migration of tumor-associated neutrophils to tumor tissues and inhibits the entry of CD4+ and CD8+ T cells into the tumor microenvironment, whereas PTEN deletion caused by different mechanism up-regulates VEGF expression, which promotes tumor angiogenesis, leading to impaired perfusion and decreased CD8+ T cell infiltration. Moreover, in some solid tumors, it is difficult for T cells to pass through an immunosuppressive tumor stroma, resulting in resistance to PD-1 blockade

Fig. 5

T cell exhaustion causes PD-1 blockade therapy resistance. PD-1 blockade promotes the secretion of cytokines, including IFN-γ and TNF, leading to the expression of ligands of inhibitory receptors, including LAG3 and TIM-3, in tumor cells and activation-induced cell death (AICD). Additionally, PD-1 blockade can attenuate the expression or activity of a series of genes and promote T cell exhaustion. Furthermore, after PD-1 blockade, tumor cells show high oxygen consumption, which causes hypoxia in the tumor microenvironment, promoting the exhaustion of T cells. Moreover, NSE1 activity in TILs is inhibited, which affects glycolysis and leads to T cell depletion

Fig. 6

PD-L1 expression changes contribute to resistance. Mutations in the JAK and EGFR genes result in the loss of PD-L1 expression, affecting antigen presentation. The lack of CXCL9, 10, and 11 expression prevents T cell chemotaxis in the tumor microenvironment, causing primary resistance. After PD-1 blockade, adaptive changes in various genes alter tumor cell metabolism, reduce MHC expression, and upregulate PD-L1, resulting in the inhibition of T cell activity and adaptive resistance

Fig. 7

Combination therapeutic strategy to enhance T cell activation and T immune cell function and infiltration. There are approximately five types of combined treatment strategies. Combinations with anti-PD-1/PD-L1 agents can induce better therapeutic effects by inducing immunogenic cell death and restoring the function of the tumor suppressor p53. We summarize the combinations with B2M, HSCs (CCR2+), HDAC, and other cells and molecules. We describe a number of ways to inhibit MDSCs and thereby enhance therapeutic efficacy. Various molecules, including IL-15, CD96, CD47, and CD137 have potential inhibitory effects. We also summarize receptor-mediated and combination therapeutic strategies for the activation of inflammatory pathways and immune cells