PD-1 suppresses development of humoral responses that protect against Tn-bearing tumors

Tn is a carbohydrate antigen uniquely exposed on tumor mucins and, thus, an ideal target for immunotherapy. However, it has been difficult to elicit protective antibody responses against Tn antigen and other tumor-associated carbohydrate antigens. Our study demonstrates this can be attributed to PD-1 immuno-inhibition. Our data show a major role for PD-1 in suppressing mucin- and Tn-specific B-cell activation, expansion, and antibody production important for protection against Tn-bearing tumor cells. These Tn/mucin-specific B cells belong to the innate-like B-1b cell subset typically responsible for T cell-independent antibody responses. Interestingly, PD-1-mediated regulation is B cell-intrinsic and CD4⁺ cells play a key role in supporting Tn/mucin-specific B-cell antibody production in the context of PD-1 deficiency. Mucin-reactive antibodies produced in the absence of PD-1 inhibition largely belong to the IgM subclass and elicit potent antitumor effects via a complement-dependent mechanism. The identification of this role for PD-1 in regulating B cell-dependent antitumor immunity to Tn antigen highlights an opportunity to develop new therapeutic strategies targeting tumor-associated carbohydrate antigens.