Translational Potential of TGFβ biology
Even though TGFβ has long been considered an important target in cancer therapy, the context in which TGFβ activity is clinically actionable has yet to be established. In the context of immunotherapy, TGFβ signaling provides multi-faceted mechanisms of immune evasion via generation of immunosuppressive cell interactions. TGFβ also regulates the DNA damage response. Faulty DNA repair is a hallmark of cancer, and specific repair defects can provide the basis for response to specific therapies, including immunotherapy. Our current goal is to identify the conditions under which TGFβ inhibition can achieve the greatest benefit.
Optimal combinations of Radiation Therapy and Immunotherapy may depend on the composition of the tumor microenvironment.
Recent studies demonstrate that TGFβ is critical to the immunological response to radiation:
Key Publications:
Vanpouille-Box, C., Diamond, J., Pilones, K. A., Zavadil, J., Babb, J. S., Formenti, S. C., Barcellos-Hoff, M. H., and Demaria, S. (2015).Transforming growth factor (TGF) β is a master regulator of radiotherapy-induced anti-tumor immunity. Cancer Research 75, 2232-2242. PMID: 25858148
Gonzalez-Junca, A., Driscoll, K., Pellicciotta, I., Du, S., Lo, C. H., Roy, R., Parry, R., Tenvooren, I., Marquez, D., Spitzer, M. H., and Barcellos-Hoff, M. H. (2019). Autocrine TGFbeta is a Survival Factor for Monocytes and Drives Immunosuppressive Lineage Commitment. Cancer Immunology Research. DOI: 10.1158/2326-6066.cir-18-0310
Key Publications:
Bouquet, S.F., A. Pal, K.A. Pilones, S. Demaria, B. Hann, R.J. Akhurst, J.S. Babb, S.M. Lonning, J.K. DeWyngaert, S. Formenti, and M.H. Barcellos-Hoff. 2011. Transforming growth factor β1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res. 17:6754-6765. PMID: 22028490
Kirshner, J., M.F. Jobling, M.J. Pajares, S.A. Ravani, A. Glick, M. Lavin, S. Koslov, Y. Shiloh, and M.H. Barcellos-Hoff. 2006. Inhibition of TGF-beta1 signaling attenuates ATM activity in response to genotoxic stress. Cancer Res. 66:10861-10868. PMID: 17090522
Bayin NS, Ma L, Thomas C, Baitalmal R., Sure A, Fansiwala K, Bustoros M, Golfinos JG, Pacione D, Snuderl M, Zagzag D, Barcellos-Hoff MH, Placantonakis D. Patient-specific screening using high-grade glioma explants to determine potential radiosensitization by a TGF-β small molecule inhibitor. Neoplasia (New York, NY). 2016;18(12):795-805. Epub Oct 24. doi: 10.1038/oncsis.2016.63.
Liu Q, Ma L, Jones T, Palomero L, Pujana MA, Martinez-Ruiz H, et al. Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining. Clin Ca Res doi 10.1101/353441.
