Douglas Fearon
Professor
M.D., Johns Hopkins University School of Medicine, 1968
dfearon@cshl.edu | (516) 367-5420
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.
Big bold dreamers
December 10, 2018
2018 Double Helix Medal honoree Dr. Larry Norton has dedicated his career to ridding the world of cancer. Under the belly of the blue whale at the American Museum of Natural History, he reminded us that big dreams can come true. Larry shared childhood memories of visiting the museum with his mother. Pulling on her...
How pancreatic cancer spreads after surgery
May 17, 2018
Cold Spring Harbor, NY — Scientists at Cold Spring Harbor Laboratory (CSHL) have solved a mystery about how pancreatic cancer spreads following surgery in patients whose tumor is successfully removed. After surgery, patients typically experience a two-week period during which their immune system is depleted as a result of a surge in post-operative stress hormone...
The immune system, unleashed
May 15, 2018
Base Pairs podcast Many stories start the same. Boy meets girl, they fall in love, and there’s a happy ending. In the story of Elizabeth “Bessie” Dashiell, that boy was John D. Rockefeller, Jr., and by all accounts they should have gotten their happily-ever-after. But Bessie was in a minor accident, getting her hand caught...
Bringing immune cells back into the cancer fight
May 4, 2018
The human immune system protects us so reliably against most bacterial infections and viruses. We owe our lives to it. So why doesn’t it just as reliably prevent us from getting cancer? Most experts agree that the immune system does indeed suppress the formation of cancers. Immune cells vanquish viruses that by some estimates cause...
One experiment: When cancer is hiding in plain sight
March 1, 2018
Everyone knows how important the immune system is—our lives utterly depend upon it. Its role in fighting bacteria and common viruses is something we take for granted. Few people know that its protection extends to viruses that can cause cancer. And yet cancer is so common. When it strikes, is the immune system letting us...
Turning off the immune system is hard. Turning it on against cancer is easier.
January 10, 2018
he immune system’s awesome power has captivated Professor Douglas Fearon throughout over 45 years of study, both as a medical doctor and as a scientist. Yet just 10 years ago, he “didn’t believe in cancer immunology,” he admits frankly. Today, cancer drugs based on the idea of harnessing the immune system’s power are helping to...
Pancreas and colon tumors reprogram the liver, causing wasting and short-circuiting body’s immune response
November 8, 2016
Many cancer patients suffer from extreme weight loss in a condition known as cachexia. The Fearon lab has found that this calorie deprivation can have profound implications for tumor immunology, allowing tumor cells to become resistant to immunotherapy.
New senior faculty join CSHL
November 10, 2014
This fall, the Lab welcomes six new faculty members. They’re a diverse group—a mix of junior and senior investigators, with research spanning across Biology. Want to know a little more? We’ll be featuring brief profiles all week. So check back for more! Professor Douglas Fearon, Cancer Where are you from? The University of Cambridge, England...
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