PD-1 marks dysfunctional regulatory T cells in malignant gliomas

Abstract

Immunotherapies targeting the immune checkpoint receptor programmed cell death protein 1 (PD-1) have shown remarkable efficacy in treating cancer. CD4+CD25hiFoxP3+ Tregs are critical regulators of immune responses in autoimmunity and malignancies, but the functional status of human Tregs expressing PD-1 remains unclear. We examined functional and molecular features of PD-1hi Tregs in healthy subjects and patients with glioblastoma multiforme (GBM), combining functional assays, RNA sequencing, and cytometry by time of flight (CyTOF). In both patients with GBM and healthy subjects, circulating PD-1hi Tregs displayed reduced suppression of CD4+ effector T cells, production of IFN-γ, and molecular signatures of exhaustion. Transcriptional profiling of tumor-resident Tregs revealed that several genes coexpressed with PD-1 and associated with IFN-γ production and exhaustion as well as enrichment in exhaustion signatures compared with circulating PD-1hi Tregs. CyTOF analysis of circulating and tumor-infiltrating Tregs from patients with GBM treated with PD-1-blocking antibodies revealed that treatment shifts the profile of circulating Tregs toward a more exhausted phenotype reminiscent of that of tumor-infiltrating Tregs, further increasing IFN-γ production. Thus, high PD-1 expression on human Tregs identifies dysfunctional, exhausted Tregs secreting IFN-γ that exist in healthy individuals and are enriched in tumor infiltrates, possibly losing function as they attempt to modulate the antitumoral immune responses.

Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses

“…We found that the cellular subsets that represented the tumor tissue exhibited an exhausted and immunosuppressive phenotype, as evidenced by the enhanced expression of multiple exhaustion markers (PD-1, CD152, and Lag-3), accumulation of IL-10-expressing immunosuppressive Treg and TAM subsets, and low expression of inflammatory cytokines (TNFα, IFNγ, and granzyme B) by tumor-infiltrating T and NK cells. The role of exhaustion markers (particularly PD-1) on Treg function remains controversial, as it was demonstrated in malignant gliomas that PD-1 hi Treg was dysfunctional and produced IFNγ (26). Others have described that PD-1 expression is correlated with more suppressive Treg phenotypes in chronic viral infection (27).…”

“…First, we focused on Tregs, given their well-established correlation with poor prognosis in various cancers, including HCC (23)(24)(25). Recent studies have also demonstrated the expression of exhaustion markers on Tregs, in particular PD-1, and their effect on Treg function (26,27). We then examined whether the Tregs expressed different immune exhaustion markers between the TIL, NIL, and PBMC groups.…”

Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

“…PD-1 hi Tregs in the TME in glioma patients have been found to be exhausted, yet capable of generating proinflammatory cytokines, such as IFN-γ (35). This suggests that one mechanism for the impaired function of anti-PD-1 antibody therapy is the presence of PD-1-expressing Tregs that can (a) bind antibody widely by subtype.…”

Biological mechanisms of immune escape and implications for immunotherapy in head and neck squamous cell carcinoma

“…In addition to the high expression of PD1 on CD8 + and CD4 + T cells, PD-L1 is expressed on 50—60% of HNSCC tumours[84,88]. While overexpression of PD-L1 inhibits tumour-directed T-cell cytotoxicity and permits immune evasion and tumour growth, prognostic significance of PD-L1 expression by tumours has been variable, correlating with worse outcomes in some cases [89—92] and improved outcome in others [93]. Regardless, blockade with an anti-PD-L1 mAb promotes immune-mediated tumour rejection and destruction of tumours [94].…”