Targeting Endoglin-Expressing Regulatory T Cells in the Tumor Microenvironment Enhances the Effect of PD1 Checkpoint Inhibitor Immunotherapy

Abstract

Purpose: Endoglin is a coreceptor for Transforming Growth factor (TGF)-β ligands that is highly expressed on proliferating endothelial cells and other cells in the tumor microenvironment (TME). Clinical studies have noted increased programmed cell death (PD)1 expression on cytotoxic T-cells in the peripheral blood of cancer patients treated with TRC105, an endoglin targeting antibody. In the current study, we investigated the combination of endoglin antibodies (TRC105 and M1043) with an anti-PD1 antibody. Experimental Design: The combination anti-endoglin/anti-PD1 antibodies was tested in four preclinical mouse models representing different stages of cancer development. To investigate the underlying mechanism, Fc-receptor knockout mice were used complemented with depletion of multiple immune subsets in mice. Tumor growth and the composition of immune infiltrate was analyzed by flow cytometry. Finally, human colorectal cancer specimens were analyzed for presence of endoglin-expressing Tregs. Results: In all models, the combination of endoglin antibody and PD1 inhibition produced durable tumor responses, leading to complete regressions in 30-40% of the mice. These effects were dependent on the presence of Fc-y receptors, indicating the involvement of antibody-dependent cytotoxic responses and the presence of CD8+ cytotoxic T cells and CD4+ T-helper cells. Interestingly, treatment with the endoglin antibody TRC105 significantly decreased the number of intratumoral regulatory T cells (Tregs). Endoglin expressing Tregs were also detected in human colorectal cancer specimens. Conclusion: Taken together these data provide a rationale for combining TRC105 and anti-PD1 therapy and provide additional evidence of endoglin's immunomodulatory role.