15. Xiaofei Li, PhD

Fibroblastic reticular cells (FRC) of tumor-draining lymph nodes (TDLN) profoundly influence host immune responses to tumors in their local nodal environment. In our study, we observed both mouse and human FRC undergo a phenotypic transformation during tumor progression in which they acquire many of the genomic and proteomic characteristics of cancer-associated fibroblasts. This phenotypic transformation of FRC appears to be largely mediated by tumor-secreted Tumor Necrosis Factor Superfamily Member 14 (TNFSF14, aka LIGHT), which acts through the human herpesvirus entry mediator (HVEM) receptor on FRC. FRC with the resultant cancer-associated fibroblasts (CAFs) phenotype facilitate further tumorigenesis by impeding the host’s anti-tumor immune response via mechanisms involving the quiescing of effector T cells, inhibition of T cell recruitment to the lymph node, and promotion of tumor cell motility. Blocking the interaction between tumor-secreted LIGHT and HVEM, either via systemic inhibition of LIGHT or deletion of either gene, effectively inhibits tumor growth. We have also observed that secretion of the chemokine CXCL12 by FRC appears to be at least partially LIGHT-dependent and critical for their immunosuppressive effect in TDLN. This effect can be effectively reversed by knocking out CXCL12, even in tumor microenvironments where normal immune function has been at least partially restored by knocking down LIGHT. Taken together, these findings provide powerful evidence that blocking the interaction between LIGHT secreted by cancer cells and its HVEM receptor on FRC could be an innovative therapeutic strategy.