1038P - Interactions of immune checkpoint blockade and regulatory T cells

Background

Immunosuppression mediated by regulatory T cells (Tregs) abrogates the response to immune checkpoint blockade (ICB). Antibody dependent cell cytotoxicity has been suggested as a mechanism by which anti- CTLA-4 Ipilimumab can overcome the cancer promoting effects of Tregs. Similarly, the relative activation of Tregs versus CD4 T cells has been implicated in the response to anti-PD1 immunotherapy. Whilst such associations have been observed within tumours, the relationship between Treg subset size prior to and across both single agent anti PD1 (sICB) and combination anti-PD1/anti-CTLA-4 (cICB) in metastatic melanoma (MM) is relatively unexplored. Here we have analysed the relative abundance of Tregs and contrasted with other subsets in the treatment of MM and associated with oncological outcomes.

Methods

Flow cytometry was used to quantify Tregs in PBMCs from 94 melanoma patients receiving either combined or single agent ICB. Anti-IgG4 was used to stain anti-PD1 and quantify Nivolumab/Pembrolizumab binding in Treg subsets. Observations were secondarily explored in scRNAseq analysis across samples (n=80).

Results

Increasing Treg proportions is associated with a decrease in CD8+ effector phenotypes prior to treatment. ICB expands the Treg subset, with a larger increase seen in single ICB. Patients with less anti-PD1 bound to Tregs in comparison to classical CD4+ T cells had a survival advantage-this effect was not seen in combination therapy. Counts of Tregs were associated with distinct gene expression profiles across T cell subsets.

Conclusions

Treg abundance in peripheral blood is correlated with reduced CD8+ cytotoxicity in melanoma patients and distinct patterns of gene expression. ICB mediated restoration of the immunosuppressive functions of Tregs may negatively impact clinical outcome but only after anti PD1 treatment alone.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

B.P. Fairfax.

Funding

MRC WIMM, Wellcome Trust.

Disclosure

All authors have declared no conflicts of interest.