Tumor derived extracellular vesicles and anti-tumor immunity in colorectal cancer.

Colorectal cancer (CRC) remains the third most common cause of cancer-related deaths in the U.S. The majority (~85%) of CRC tumors are non-immunogenic, i.e. they lack a significant number of infiltrating T cells, and are typically unresponsive to the immune-checkpoint inhibitor based therapies that have dramatically changed the way we treat many cancer patients. T cells isolated from non-immunogenic, microsatellite stable (MSS) CRC have lower levels of the CD28 protein, which provides a co-stimulatory signal required for T cell activation, trafficking, proliferation, differentiation and cytotoxic activity. We are testing the following hypothesis that extracellular vesicles (EVs) containing immunosuppressive microRNAs secreted by CRC cells suppress host T cell activity locally and in tumor draining lymph nodes, resulting in a deficient immune response that allows for increased tumor progression and growth. Results from this study will fundamentally advance our knowledge of how cancer cells modulate and suppress the immune response, provide novel targets, and form the basis for a new anti-cancer therapeutic strategy.

Recent Publications

Gates TJ, Wangmo D, Zhao X, Subramanian S. (2023). Allogeneic Tumor Cell-Derived Extracellular Vesicles Stimulate CD8 T Cell Response in Colorectal Cancer. Molecular Therapy - Oncolytics. 31. 100727. 10.1016/j.omto.2023.100727. 

Prakash A, Gates TJ, Zhao X, Wangmo D, Subramanian S. (2022). Tumor-derived extracellular vesicles in the colorectal cancer immune environment and immunotherapy. Pharmacology & Therapeutics. 241. 108332. 10.1016/j.pharmthera.2022.108332.

Zhao X, Yuan C, Wangmo D, Subramanian S. Tumor-Secreted Extracellular Vesicles Regulate T-Cell Costimulation and Can Be Manipulated To Induce Tumor-Specific T-Cell Responses. Gastroenterology. 2021;161(2):560-574.e11. doi:10.1053/j.gastro.2021.04.036

Zhao X, Kassaye B, Wangmo D, Lou E, Subramanian S*. Tumor-draining lymph nodes resection and chemotherapy have diverse impacts on cancer immunotherapies doi:https://doi.org/10.1101/664912 iScience 2020

Rieth JM, Subramanian S*. Mechanisms of intrinsic tumor resistance to cancer immunotherapy. Int J Mol Biosci 2018 2: 19 E1340.

Zhao X, May A, Lou E, Subramanian S*. Genotypic and phenotypic signatures to predict immune checkpoint blockade therapy response in patients with colorectal cancer. Translational Res. 2018 196:62-70.

Zhao X, Li L, Starr T, Subramanian S*. Tumor location impacts immune response mouse models of colon cancer. Oncotarget 2017 8:54775-54787

Zhao X and Subramanian S*. Intrinsic resistance of solid tumors to immune checkpoint blockade therapy. Cancer Research 2017 77: 817-822