We study CD8+ T cell differentiation, and immunosuppression within the tumor microenvironment. Since the CD8+ T cell is the primary mediator of anti-tumor immunity, the two themes are related. We have developed mouse models to study
(1) the development of the memory CD8+ T cell, and
(2) a tumoral stromal cell that is found in all human carcinomas and a variety of other sterile inflammatory lesions. In our CD8+ T cell studies, we have shown that a subset of effector CD8+ T cells maintain a replicative function, which will help us now to consider strategies for preserving this essential aspect of the CD8+ T cell response in adoptive T cell therapy for cancer. For our tumoral stromal cell work, we have just found that conditional ablation of a single stromal cell type abolishes immunosuppression within the tumor microenvironment and permits immunological control of tumor growth. We seek to apply this finding to improving therapeutic tumor vaccination.
BAC transgenic mice ; bacterial artificial chromosome
Denton AE, Roberts EW, Linterman MA, Fearon DT. Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells. Proc Natl Acad Sci U S A. 2014 Aug 4.
Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, Teichmann SA, Janowitz T, Jodrell DI,Tuveson DA, Fearon DT. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20212-7.
Roberts EW, Deonarine A, Jones JO, Denton AE, Feig C, Lyons SK, Espeli M, Kraman M, McKenna B, Wells RJ, Zhao Q, Caballero OL, Larder R, Coll AP, O'Rahilly S, Brindle KM, Teichmann SA, Tuveson DA, Fearon DT. Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia. J Exp Med. 2013 Jun 3;210(6):1137-51.
Thaventhiran JE, Fearon DT. Control of HIV infection: escape from the shadow of Blimp-1. Eur J Immunol. 2013 Feb;43(2):323-6.
Thaventhiran JE, Hoffmann A, Magiera L, de la Roche M, Lingel H, Brunner-Weinzierl M, Fearon DT. 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. 2012 Aug 14;109(33)
Yeo CJ, Fearon DT. T-bet-mediated differentiation of the activated CD8+ T cell. Eur J Immunol. 2011 Jan;41(1):60-6
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Suppression of anti-tumor immunity by stromal cells expressing fibroblast activation protein-alpha, Science 2010 330:827–30
Bannard O, Kraman M, Fearon DT. Secondary replicative function of CD8+ T cells that had developed an effector phenotype, Science 2009 323:505 9:
Heffner M, Fearon DT. Loss of T cell receptor-induced Bmi-1 in the KLRG1+ senescent CD8+ T lymphocyte, Proc Natl Acad Sci USA 2007 104:13414 9:
Carr JM, Carrasco MJ, Thaventhiran JE, Bambrough PJ, Kraman M, Edwards AD, Al-Shamkhani A, Fearon DT. CD27 mediates interleukin-2-independent clonal expansion of the CD8+ T cell without effector differentiation”, Proc Natl Acad Sci USA 2006103:19454 9: