Douglas Fearon
Professor
M.D., Johns Hopkins University School of Medicine, 1968
dfearon@cshl.edu | (516) 367-5420 (p)
I’m studying how to harness the power of the immune system to fight cancer. Our underlying premise is that the microenvironment within a tumor suppresses the immune system. We have found a way to eliminate this suppression in the mouse model of pancreatic cancer, which has led to development of a drug for human pancreatic cancer that will enter phase 1 clinical trials in 2015.
The Fearon laboratory studies the interaction between cancer and the immune system. Our underlying premise is that the tumor microenvironment is immune suppressive because cancer cells elicit responses characteristic of wound healing and tissue regeneration. This approach has led to the finding that activated fibroblasts in the tumor stroma mediate immune suppression in several mouse models of cancer, including the autochthonous model of pancreatic ductal adenocarcinoma of the Tuveson lab. Our understanding of the basis of immune suppression is evolving, but we know that it involves the production of the chemokine, CXCL12, by the fibroblastic stromal cells, binding of this CXCL12 by pancreatic cancer cells, and exclusion of T cells from the vicinity of the cancer cells. T cell exclusion, which also occurs in several types of human adenocarcinomas, causes antagonists of T cell checkpoints to be ineffective, despite the presence of cancer-specific CD8+ T cells. This immune suppression is interrupted by administering AMD3100, an inhibitor of CXCR4, the receptor for CXCL12, which leads to the rapid accumulation of T cells amongst cancer cells, thereby uncovering the efficacy of anti-PD-L1 and eliminating cancer cells. Since human pancreatic cancer has certain immunological characteristics of the mouse model, a phase 1 clinical trial of AMD3100 in patients with pancreatic cancer will be initiated in 2015. Some of our next steps are to determine the biological process that causes cancer cells to express non-mutated, shared antigens, and the means by which dormant metastases escape immune elimination.
Feig, C. and Jones, J. O. and Kraman, M. and Wells, R. J. B. and Deonarine, A. and Chan, D. S. and Connell, C. M. and Roberts, E. W. and Zhao, Q. and Caballero, O. L. and Teichmann, S. A. and Janowitz, T. and Jodrell, D. I. and Tuveson, D. A. and Fearon, D. T. (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 110(50) pp. 20212-20217.
Roberts, E. W. and Deonarine, A. and Jones, J. O. and Denton, A. E. and Feig, C. and Lyons, S. K. and Espeli, M. and Kraman, M. and McKenna, B. and Wells, R. J. B. and Zhao, Q. and Caballero, O. L. and Larder, R. and Coll, A. P. and O'Rahilly, S. and Brindle, K. M. and Teichmann, S. A. and Tuveson, D. A. and Fearon, D. T. (2013) Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia. Journal of Experimental Medicine, 210(6) pp. 1137-1151.
Thaventhiran, J. E. and Hoffmann, A. and Magiera, L. and de la Roche, M. and Lingel, H. and Brunner-Weinzierl, M. and Fearon, D. T. (2012) Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8+ T cell. Proc Natl Acad Sci U S A, 109(33) pp. E2223-9.
Kraman, M. and Bambrough, P. J. and Arnold, J. N. and Roberts, E. W. and Magiera, L. and Jones, J. O. and Gopinathan, A. and Tuveson, D. A. and Fearon, D. T. (2010) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science, 330(6005) pp. 827-30.
Bannard, O. and Kraman, M. and Fearon, D. T. (2009) Secondary replicative function of CD8+ T cells that had developed an effector phenotype. Science, 323(5913) pp. 505-9.
Additional materials of the author atCSHL Institutional Repository