Cyclophosphamide enhances the anti-tumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness

ABSTRACT: Immune checkpoint blockade (ICB) therapy is a standard treatment option for many malignancies, but it is only effective in a subset of patients. Combination strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoidinduced TNFR-related (GITR) protein with agonist antibodies has shown efficacy in preclinical models, but GITR engagement does not control growth of advanced poorly immunogenic murine tumors such as B16 melanoma and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) preferentially depletes regulatory T cells (Tregs) and expands tumor-specific effector T cells (Teffs) via homeostatic proliferation. Additionally, CTX directly induces tumor cell death, thereby releasing antigen to prime Teffs in a lymphopenic environment where there are fewer Tregs. GITR agonism has a net inhibitory effect on Tregs and yet activates Teff. We therefore hypothesized that CTX treatment prior to GITR agonism would promote potent anti-tumor immunity. Here we show that the combination of CTX and GITR agonism robustly controls tumor growth in several clinically relevant mouse models. Mechanistically, we show that the combination therapy causes tumor cell death, clonal expansion of highly active and terminally differentiated CD8+ T cells, and depletion of regulatory T cells by AICD. Control of tumor growth was also associated with the presence of an expanded population of highly activated tumor-infiltrating oligoclonal CD8+ T cells that lead to a global contracted TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemo-immunotherapeutic approach that warrants further clinical investigation.

ORGANISM(S): Mus musculus

PROVIDER: GSE182292 | GEO | 2021/11/18

REPOSITORIES: GEO