Tumor immunotherapy has revolutionized cancer treatment, with immune checkpoint blockade (ICB) therapy being the standard of care across a growing number of cancer types. Antibodies targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) have exhibited durable clinical benefit in patients; however, only a subset of patients respond to these treatment modalities, and the mechanisms underlying these clinical differences in response remain elusive. While multiple genomic and immunological features based on analysis of pretreatment tumor biopsies have shown a correlation with response to ICB therapies, robust predictive biomarkers have not yet been clearly identified. Thus, defining the mechanisms of therapeutic responses and robust biomarkers predictive of response and resistance would be beneficial to accurately stratify patients for ICB therapies and possibly to enrich patients that would benefit from those therapies. Given the significance of PD-1 in the immune response and its dual roles as both an activation and exhaustion marker, clarifying the function and mechanism of PD-1-positive tumor-infiltrating lymphocytes (TILs) in regulating antitumor immunity is highly appealing. A recent study by Kumagai et al.1 proposed that the balance between PD-1 expression in effector CD8+ T cells and in regulatory T (Treg) cells in the tumor microenvironment (TME) is a more robust predictor of the clinical efficacy of PD-1 blockade therapies than other predictors, such as PD-L1 expression, tumor mutational burden (TMB) and some peripheral blood mononuclear cell (PBMC) biomarkers.
PD-1+CD8+ T cells are more enriched in the tumors of patients who respond to PD-1 blockade therapies than in those of nonresponding patients; however, some patients harboring a high frequency of PD-1+ CD8+ T cells still fail to respond to these therapies. Discerning the mechanisms that prevent an effective immune response in nonresponders (resistance mechanism) is equally important for PD-1 blockade therapies. The functional phenotype of CD8+ T cells is not only driven by antigen stimulation but also shaped by cell-extrinsic inhibitory mechanisms, such as regulatory T (Treg) cells. Treg cell infiltration into tumor tissues promotes tumor progression by supporting immune evasion and preventing the antitumor immune response. Similar to tumor-infiltrating CD8+ T cells, Treg cells also express immune checkpoint proteins, including PD-1, suggesting that antibodies targeting PD-1 could influence both cell types. However, the correlation between tumor-infiltrating PD-1+ Treg cells and the clinical outcome of PD-1 blockade therapies is presently not clear. A study revealed that a subset of Treg cells in human glioblastoma tissues with high PD-1 expression have a dysfunctional, exhausted phenotype, releasing interferon-γ (INF-γ) and exhibiting reduced immunosuppressive function.9 Moreover, PD-1+ Treg cells exhibiting enhanced proliferation and immunosuppressive activity were reported to be enriched in tumors of hyperprogressive disease (HPD) patients after PD-1 blockade treatment.10 Reasonably, PD-1 blockade therapies might reinforce the immunosuppressive function of PD-1+ Treg cells. Consistently, in this manuscript, Kumagai et al.1 demonstrated that PD-1 expression by Treg cells in the TME of nonresponders was more enriched than that in responders and associated with shorter PFS, as observed in HPD. In Treg cells, the authors found that the PD-1/PD-L1 axis inhibited the TCR and CD28 signaling pathways through recruitment and phosphorylation of SHP2, as shown in CD8+ T cells, and PD-1/PD-L1 blockade released restrained TCR and CD28 signals, thereby enhancing the immunosuppressive function of Treg cells. Therefore, high PD-1 expression by Treg cells in the TME plays an important role in the mechanism of resistance to PD-1 blockade therapies, with the activation of PD-1+ Treg cells potently suppressing the proliferation of CD8+ effector T cells and dampening the effective antitumor response (Fig. 1C).
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