Functional Interrogation of Germinal Center Independent Memory B Cells in Head and Neck Cancer

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Current immunotherapies aim to reinvigorate dysfunctional or “exhausted” T cells, and while immunotherapies like anti-PD1 have improved the prognosis of patients with head and neck squamous cell carcinoma (HNSCC), most patients fail to produce a durable response. B cells represent a new possible target as they correlate with increased patient survival and immunotherapeutic response. Further, B cells directly potentiate the antitumor immune response locally and peripherally by producing tumor-specific antibodies that assist in cytotoxic effector functions that mediate tumor cell clearing, and through the generation of antigen-specific memory B cells (MBCs). Together, these data highlight MBCs as a promising target for new immunotherapeutic options to complement T-cell centric therapies; however, there is a clear knowledge gap in mechanistically understanding MBC function in the tumor microenvironment. MBCs are a heterogenous population with functionally distinct subsets and may be generated either from germinal center (GC)-dependent reactions or GC-independent reactions, that often predominate in chronic infections. In HNSCC, GC-independent MBCs accumulate in patient peripheral blood and tumors and correlate with advanced stage disease. Chronic antigen stimulation promotes the development of GC-independent MBCs, which are dysfunctional compared to GC-dependent MBCs i.e. hyporesponsive to BCR stimulation, impaired differentiation to antibody secreting cells, and poor effector (IgG) antibody production. Moreover, we find that GC-independent MBCs express high levels of inhibitory receptors, such as PD-1 and FcRL5, further suggesting this population is functionally impaired in the tumor microenvironment. Importantly, despite low antibody production, GC-independent MBCs predominantly produce IgG antibodies, posing this MBC subset as an antigen specific population that can contribute to antitumor immunity through the production of tumor reactive antibodies. Our overarching hypothesis is that GC- independent MBCs are a tumor-specific B cell subset in the tumor microenvironment that can be therapeutically bolstered to secrete tumor-reactive antibodies. This proposal will (1) identify tumor reactive GC-independent MBCs in the tumor microenvironment and assess their potential to contribute to tumor cell clearance; and (2) interrogate therapeutic modulation of these populations, evaluating response to standard of care immunotherapies i.e. anti-PD1 treatment and combinatorial FcRL5 blockade. Successful completion of this proposal will provide preclinical rationale for B-cell centric therapies in tandem with current immunotherapy strategies for the treatment of solid tumors.