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Douglas Fearon

Douglas Fearon

Professor
Cancer Center Member

M.D., Johns Hopkins University School of Medicine, 1968

dfearon@cshl.edu | 516-367-5420

Faculty Profile

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.

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Selected Publications

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

CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response

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

Cancer cell CCR2 orchestrates suppression of the adaptive immune response.

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

CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response

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

Autophagy Promotes Immune Evasion of Pancreatic Cancer by Degrading MHC-I

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

All Publications

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

Pancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy

4 Sep 2020 | bioRxiv
Wang, Zhikai, Yan, Ran, Li, Jiayun, Gao, Ya, Moresco, Philip, Yao, Min, Hechtman, Jaclyn, Weiss, Matthew, Janowitz, Tobias, Fearon, Douglas

A framework for advancing our understanding of cancer-associated fibroblasts

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

Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology.

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

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