Douglas Fearon FRS is the Sheila Joan Smith Professor of Immunology at the University of Cambridge. He is also a senior group leader at Cancer Research UK Cambridge Research Institute.
Over the past 40 years, Dr Douglas Fearon has made contributions to our understanding of innate immunity, B cell signal transduction, memory T cells, and, most recently, cancer immunology. During the past 10 years, Dr Fearon has trained 15 PhD and MB/PhD students at the University of Cambridge. Former post-doctoral fellows now have faculty or staff positions at outstanding institutions such as Harvard Medical School, the NIAID, University of Cambridge, King’s College London, University of Leicester, and the University of Ryukyus. His past work with a genetically engineered mouse that enables the conditional depletion of cancer associated fibroblasts led to the identification of an essential role for this stromal cell type and one of its products, CXCL12, in immune suppression by the tumor microenvironment. 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 KPC model of pancreatic ductal adenocarcinoma. 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. Our next steps are to determine the process that enables cancer cells to capture CXCL12, the means by which ligation of CXCR4 by cancer cell-associated CXCL12 prevents the accumulation of intratumoral T cells, and the normal biological event for which this means for creating an immune privileged site evolved.SCIENTIFIC PROGRAMME