Intratumoral Recall of Childhood Vaccine-Specific CD4⁺ T cells Coordinates Type I and II Antitumor Immunity

ABSTRACT

CD4⁺ T cells are key contributors to cancer immune surveillance. Here we report that childhood vaccine associated antigens engage simultaneous antitumor functions of CD8⁺ T cells and eosinophils via intratumor vaccine-specific CD4⁺ T cell recall. Prior vaccination against poliovirus potentiates antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Antitumor effects of recall antigens were mediated by CD4⁺ T cells, independent of CD40L signaling, and were dependent on eosinophils and CD8⁺ T cells. Recall antigen therapy caused marked tumor infiltration of type 2 innate lymphoid cells (ILC2s) expressing granzyme B and PD1 and eosinophils, coinciding with decreased proportions of intratumor Tregs. A pan-cancer analysis revealed an inverse relationship between intratumor eosinophils and Tregs, but not CD4⁺ or CD8⁺ T cells. This work defines cancer immunotherapy potential of childhood vaccines and implicates type II immunity in CD4⁺ T cell cancer immune surveillance.