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.
Cold Spring Harbor Laboratory 2022 Ph.D.’s
May 1, 2022
The School of Biological Sciences awarded Ph.D. degrees to ten students this year. Here are some stories and memories from their time at CSHL.
Deactivating pancreatic cancer’s protective coat of arms
February 17, 2022
Find out how cancer cells shield themselves from the immune system using a coat of armor and confusing signals.
Pushing past pancreatic tumors’ defenses
February 16, 2022
A complex of proteins secreted by tumor cells can immobilize an important component of the immune system.
Giving the immune system a double boost against cancer
October 30, 2020
Immunotherapy enhances the body’s own defenses to kill cancer. A new regimen may increase the utility of these types of drugs.
Big bold dreamers
December 10, 2018
Dreamers drive discoveries. CSHL honors its many scientists making big impacts in their respective fields.
Base Pairs Episode 15.5: Cellular hide and seek
June 15, 2018
Learn how William Coley's daughter founded the Cancer Research Institute, Professor Fearon on the immune system, and white blood cells on screen.
How pancreatic cancer spreads after surgery
May 17, 2018
Researchers have solved a mystery about how pancreatic cancer spreads
How deadly cancer spreads after surgery
May 17, 2018
Scientists have solved an important mystery about how pancreatic cancer spreads to the liver even after a successful surgery.
The immune system, unleashed
May 15, 2018
Cancer immunotherapy has a long and storied history, one that begins with a young woman suffering from a pain in her hand
Base Pairs Episode 15: The immune system unleashed
May 15, 2018
Cancer immunotherapy has a long and storied history, one that begins with a young woman suffering from a pain in her hand.
AMD3100/Plerixafor overcomes immune inhibition by the CXCL12-KRT19 coating on pancreatic and colorectal cancer cells.
26 Mar 2021 | British Journal of Cancer
Fearon, Douglas, Janowitz, Tobias
17 Nov 2020 | Proceedings of the National Academy of Sciences of USA | 117(46):28960-28970
Biasci, D, Smoragiewicz, M, Connell, C, Wang, Z, Gao, Y, Thaventhiran, J, Basu, B, Magiera, L, Johnson, T, Bax, L, Gopinathan, A, Isherwood, C, Gallagher, F, Pawula, M, Hudecova, I, Gale, D, Rosenfeld, N, Barmpounakis, P, Popa, E, Brais, R, Godfrey, E, Mir, F, Richards, F, Fearon, D, Janowitz, T, Jodrell, D
5 Oct 2020 | Journal of Experimental Medicine | 217(10)
Fein, Miriam, He, Xue-Yan, Almeida, Ana, Bružas, Emilis, Pommier, Arnaud, Yan, Ran, Eberhardt, Anaïs, Fearon, Douglas, Van Aelst, Linda, Wilkinson, John, Dos Santos, Camila, Egeblad, Mikala
10 Jul 2020 | medRxiv
Biasci, D, Smoragiewicz, M, Connell, C, Wang, Z, Gao, Y, Thaventhiran, J, Basu, B, Magiera, L, Johnson, I, Bax, L, Gopinathan, A, Isherwood, C, Gallagher, F, Pawula, M, Hudecova, I, Gale, D, Rosenfeld, N, Barmpounakis, P, Popa, E, Brais, R, Godfrey, E, Mir, F, Richards, F, Fearon, D, Janowitz, T, Jodrell, D
May 2020 | Nature | 581(7806):100-105
Yamamoto, K, Venida, A, Yano, J, Biancur, D, Kakiuchi, M, Gupta, S, Sohn, A, Mukhopadhyay, S, Lin, E, Parker, S, Banh, R, Paulo, J, Wen, K, Debnath, J, Kim, G, Mancias, J, Fearon, D, Perera, R, Kimmelman, A
Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack
25 Jan 2022 | Proceedings of the National Academy of Sciences of USA | 119(4):e2119463119
Wang, Zhikai, Moresco, Philip, Yan, Ran, Li, Jiayun, Gao, Ya, Biasci, Daniele, Yao, Min, Pearson, Jordan, Hechtman, Jaclyn, Janowitz, Tobias, Zaidi, Raza, Weiss, Matthew, Fearon, Douglas
4 Sep 2020 | bioRxiv
Wang, Zhikai, Yan, Ran, Li, Jiayun, Gao, Ya, Moresco, Philip, Yao, Min, Hechtman, Jaclyn, Weiss, Matthew, Janowitz, Tobias, Fearon, Douglas
20 Mar 2020 | Nature Reviews Cancer | 20(3):174-186
Sahai, E, Astsaturov, I, Cukierman, E, DeNardo, D, Egeblad, M, Evans, R, Fearon, D, Greten, F, Hingorani, S, Hunter, T, Hynes, R, Jain, R, Janowitz, T, Jorgensen, C, Kimmelman, A, Kolonin, M, Maki, R, Powers, R, Pure, E, Ramirez, D, Scherz-Shouval, R, Sherman, M, Stewart, S, Tlsty, T, Tuveson, D, Watt, F, Weaver, V, Weeraratna, A, Werb, Z
Embryonic FAP(+) lymphoid tissue organizer cells generate the reticular network of adult lymph nodes
19 Jul 2019 | Journal of Experimental Medicine | 216(10):2242-2252
Denton, A, Carr, E, Magiera, L, Watts, A, Fearon, D
2 Jul 2019 | Proceedings of the National Academy of Sciences of USA | 116(27):13490-13497
Nayar, Saba, Campos, Joana, Smith, Charlotte, Iannizzotto, Valentina, Gardner, David, Mourcin, Frédéric, Roulois, David, Turner, Jason, Sylvestre, Marvin, Asam, Saba, Glaysher, Bridget, Bowman, Simon, Fearon, Douglas, Filer, Andrew, Tarte, Karin, Luther, Sanjiv, Fisher, Benjamin, Buckley, Christopher, Coles, Mark, Barone, Francesca