PD-1 regulation of protective immune responses to Tn+ tumors

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

DESCRIPTION (provided by applicant): The immune system plays an important role in the elimination of tumors. There have been studies exploring the potential use of tumor vaccines to elicit a better adaptive immune response against tumor antigens. Cancer cells often have aberrant glycosylation of surface molecules that lead to glycan antigens that are not normally seen by the immune system. These are referred to as tumor associated carbohydrate antigens (TACAs). An example of a TACA is the Thomsen-nouvelle (Tn) antigen which is expressed by a variety of adenocarcinomas. The mechanisms regulating B cell responses to Tn and other TACAs are not well understood. By having an understanding on what components regulate B cell responses to carbohydrate antigens, superior vaccines can be developed to elicit an enhanced protective response to TACAs. PD-1 (programmed cell death 1) is part of the B7:CD28 family of receptors found on antigen activated B and T cells. It negatively regulates antigen receptor signaling and thereby often suppresses adaptive immune responses. Our preliminary data shows that PD-1 knock out (PD1-/-) mice immunized with a Tn-bearing mucin (de- sialylated bovine submaxillary mucin, dBSM) have significantly increased survival relative to wild type mice when challenged with a Tn-bearing mammary tumor (TA3-HA). PD1-/- mice had increased IgM but not IgG antibodies (Abs) against dBSM and TA3-HA cells. It is therefore hypothesized that PD-1 suppresses anti-tumor protection elicited by dBSM immunization through inhibiting B cell production of Tn specific IgM Abs. The originality of this project is tha there have not been any studies evaluating the role of PD1 on the regulation of B cell responses to TACAs. This proposed study will determine the mechanisms by which PD-1 regulates anti- Tn Ab responses and the importance of Tn-specific Abs in eliciting tumor protection that is elicited by Tn+ mucin-based immunization. In Aim 1, the role that PD-1 plays in regulating B cell responses to Tn antigen will be determined. In Aim 2, the mechanism(s) by which dBSM immunization contributes to enhanced protection against TA3-HA tumors in PD-1-/- mice will be determined. At the end of these studies we will have a better understanding of how PD-1 regulates B cells responses against Tn and the extent to which Tn specific Ab influence tumor immunity. Gaining an understanding of how to elicit better protection against TACAs will open the door to producing effective cancer vaccines.