Leveraging B cell specificities for tumor glycans to elicit potent anti-tumor immunity

SUMMARY Tumor associated carbohydrate antigens (TACAs) are aberrant glycosylation products that are expressed on cancer cells but absent on most normal cells. Their expression is typically associated with metastasis, poor prognosis, and reduced overall survival. Tn antigen (N-acetylgalactosamine O-linked to a serine or threonine) is a TACA often found on cancer mucins. We have investigated the regulation of B cell responses to Tn- and other TACA-bearing mucins using a mouse model. Our progress has shown that specificities for TACAs, including Tn, are highly enriched in the innate B (B1) cell population in mice. We have also found that B cell-intrinsic PD-1 expression potently suppresses tumor-protective TACA-specific antibody (Ab) responses and that CD4+ cells are required for the increased responses that are observed in the context of PD-1 inhibition. Finally, we identified a Tn-specific IgM monoclonal Ab that has significant and broad anti-tumor activity in vivo. Our understanding of the mechanisms regulating Ab responses to Tn and other TACAs is very limited. Similarly, our understanding of the mechanisms by which these Abs effectively kill cancer cells is incomplete. These critical gaps in knowledge must be filled in order to harness the protective capacity of TACA-reactive B cells and the Abs that they produce. The central hypothesis of this proposal is that B cells with natural specificities for TACAs play a critical role in the effective anti-tumor immune response to cancers. Our key objectives are to: 1) Determine the mechanisms by which CD4+ T cells support TACA-specific Ab responses and the extent to which PD-1 inhibition alters the diversity of the Tn-specific B cell response (Aim 1), 2) Identify the mechanisms by which Tn-specific IgM promotes both tumor cell killing and adaptive anti-tumor immune responses (Aim 2), and 3) Examine the repertoire of Tn-specific B cells in humans and identify broadly reactive Tn-specific Abs with tumor-killing potential (Aim 3). The findings emanating from these studies are expected to reveal novel opportunities to 1) harness the anti-tumor potential of B cells with specificities for cancer-expressed glycans and 2) leverage broadly-reactive TACA Abs for their ability to promote highly specific adaptive and dynamic immune responses targeting TACA-associated peptides.