210P - Anti-CTLA-4 overcomes inhibitory effect of PD1high regulatory T cell on circulating antitumor CD4+ Th1 response in patients treated by anti-PD(L)-1

Background

Evidence supports the crucial involvement of CD4+ T cells in anti-tumor immunity and immunotherapy (IO). In this study, we studied the systemic antitumor CD4 Th1 response in patients receiving anti-PD(L)-1 therapy.

Methods

Patients with metastatic cancers receiving anti-PD(L)-1 therapy (n=117) were enrolled in an immunomonitoring cohort (ITHER study, NCT02840058). Blood samples were collected at baseline, one month, and three months after IO. Tumor-reactive CD4+ Th1 response was measured by IFN-y ELISPOT, after lymphocytes culture with pan-HLA class II binding peptides derived from telomerase, as previously described (Laheurte et al., BJC 2019, Nardin et al., J Inves Dermatol 2022). Phenotypic analysis of circulating immune cells was performed by flow cytometry.

Results

While an expansion of circulating antitumor CD4+ Th1 response was associated with favorable clinical outcomes, its impairment after IO appeared deleterious. Searching for an explanation for this unexpected loss of tumor-specific CD4+ T cells, we ruled out a potential apoptotic effect resulting from activation of the PD1 signaling. However, we identified a role of Foxp3+Treg subset overexpressing PD1 (PD1^high Treg). Indeed, a high level of circulating PD1^high Treg was preferentially found in these patients. PD1^high Treg displayed overexpression of inhibitor receptors such as CTLA-4, ICOS, and GITR, which are upregulated after IO. The addition of anti-CTLA-4 mAb in vitro restored the function of antitumor CD4+ T cells, supporting the suppressive effect exerted by circulating PD1^high Treg during IO.

Conclusions

Thus, activation of PD1^high Treg inhibits antitumor T cell response in patients treated by anti-PD(L)-1 therapy. These results support blood-based monitoring of tumor-reactive CD4+ Th1 response together with PD1^High Treg for patient management and treatment decision.

Clinical trial identification

NCT02840058.

Legal entity responsible for the study

UMR1098.

Funding

Ligue contre le cancer, the Bourgogne Franche Comté regional council, the ARC and the Cancéropôle EST.

Disclosure

All authors have declared no conflicts of interest.