Exploring Regulators of Anti-Tumor Immunity: Chorionic Gonadotropin Beta & Major Vault Protein

Abstract

Checkpoint immunotherapy has become a pillar of cancer treatment over the past decade. Immune checkpoint inhibitors (ICIs) have been highly efficacious for many patients, but ultimately many patients do not achieve durable responses and response rates remain variable across cancers and indications. These remain significant challenges in the field, as the patterns of response and resistance and the factors that influence them remain incompletely understood. Here I describe two proteins associated with tumor-immune interactions and response to ICIs. I identify that chorionic gonadotropin beta 7 (CGB7) is expressed widely across cancers and is associated with hallmarks of immune evasion and decreased survival probability in advanced urothelial carcinoma patients undergoing treatment with ICIs. Random survival forest modeling reveals that CGB7 is predictive of decreased survival probability in the context of ICI treatment. This supports the clinical value of CGB7 as a biomarker of immune evasion and resistance to checkpoint immunotherapy. I also describe associations between Major Vault Protein (MVP) and increased response to ICIs in melanoma. In an immunocompetent model, MVP expression in both the host and in the tumor increases survival probability in vivo. Tumoral expression of MVP influences survival in an immune-dependent manner. Single cell RNA-sequencing of tumors from an immunocompetent model reveals that tumor MVP expression is associated with increased abundance of effector CD8+ T cells expressing hallmarks of exhaustion, suggesting a potential mechanism for MVP in protecting effector CD8+ T cells against dysfunction. Taken together, this work identifies both CGB7 and MVP as valuable biomarkers and/or therapeutic targets associated with blunted or augmented anti-tumor immunity in cancer, respectively.