Distinct immune microenvironment profiles of therapeutic responders emerge in combined TGF beta/PD-L1 blockade-treated squamous cell carcinoma

Strait et al describe distinct immune microenvironment profiles of responders versus non-responders to combined TGF-beta/PD-L1 blockade in mouse models of squamous cell carcinoma (SCC). The results emphasize the potential of combined TGF-beta/PD-L1 targeting and provide important clues to guide personalized SCC immunotherapy. Transforming growth factor beta (TGF beta) and programmed death-ligand 1 (PD-L1) are often overproduced in refractory squamous cell carcinoma (SCC). We examined spatial patterns of PD-L1(+) cells in mouse and human SCCs and found that PD-L1 was primarily expressed on infiltrating leukocytes. Although combined TGF beta and PD-L1 blockade are undergoing cancer clinical trials, there are no predictive markers for therapeutic responders. To address this, we used both a small molecule TGF beta inhibitor in combination with anti-PD-L1 and a bifunctional fusion protein targeting both TGF beta and PD-L1 to treat mouse SCCs and found TGF beta inhibition enhanced PD-L1 blockade-induced tumor eradication in multiple tumor models. Furthermore, we identified distinct cell populations of responders and non-responders to bintrafusp alfa, with responders showing a shift toward a more immune-permissive microenvironment. The cellular and molecular signatures of responders versus non-responders to combined TGF beta and PD-L1 blockade provide important insights into future personalized immunotherapy in SCC.

Automated summary

Strait et al. identified distinct immune microenvironment profiles of responders versus non-responders to combined TGF-beta/PD-L1 blockade in mouse models of SCC, highlighting the potential of targeted therapy and providing important insights into personalized immunotherapy for SCC.