Stromal Cell Immune Regulation in the Microenvironment

Until recently, effective immunotherapy for the treatment of hematologic malignancies has been observed largely within the context of graft-versus-leukemia effects after allogeneic stem cell transplantation. The introduction of checkpoint inhibitors and chimeric antigen receptor T cells to the treatment of hematologic malignancies have resulted in remarkable responses in some patients but therapy still fails in a significant proportion. It is becoming increasingly clear that tumors and their stromal microenvironment possess an array of mechanisms to subvert effective immune responses. This session will discuss recent advances fostering the understanding of how tumor and stromal cells act to regulate immunity and how therapeutic interventions targeting these suppressive pathways may be harnessed to improve immunotherapy outcomes.

Dr. Kai Wucherpfennig will discuss therapeutic approaches to deal with resistance to cancer immunotherapy.  In particular, the presentation will focus on a novel mAb his lab has developed that inhibits an escape pathway from natural killer (NK) cell-mediated tumor immunity. Tumor cells express the stress ligands MICA and MICB that are recognized by the NKG2D receptor on NK cells and CD8 T cells.  Escape is mediated through proteolytic shedding of MICA and MICB by tumor cells.  His research has found that inhibition of proteolytic shedding of MICA and MICB with a mAb induces anti-tumor immunity against metastases.

Dr. Melody Swartz will discuss lymphatic activation in the tumor microenvironment and its role on overall immunity. She will also describe how knowledge gained from understanding lymphatic control could influence the development of novel immunotherapeutic approaches and in vitro model systems that could serve as the platform for studying the perfused tumor microenvironment.

Dr. Ivan Maillard will review emerging evidence supporting a critical role for Notch ligands expressed by specialized subsets of non-hematopoietic stromal cells in secondary lymphoid organs, both during T and B cell immune responses and in lymphoma pathogenesis. Stromal Notch ligands play an essential role to prime pathogenic T cells through Notch signaling at the onset of graft-versus-host disease. Alloreactive T cells interact with Notch ligands in stromal cell niches within days after bone marrow transplantation, a finding of major immunobiological and translational significance. Moreover, many mature B and T cell lymphomas demonstrate oncogenic Notch activation as a result of lymphoma cell interactions with microenvironmental Notch ligands in secondary lymphoid organs, borrowing from the playbook of normal lymphocytes. Thus, stromal Notch ligands represent a new regulatory input relevant to multiple disease conditions in hematology.