Adoptive co-transfer of tumor specific CD4⁺ T cells awakens host protective immunity to MHC-II^- ovarian cancer through CD40-mediated licensing of dendritic cells and CCL5 secretion. (131.14)

Abstract

The effect of adoptive cell transfer (ACT) on endogenous anti-tumor immunity remains largely unknown. We previously showed that transferring tumor-primed T cells into tumor-bearing mice awakened endogenous antitumor mechanisms and induced the rejection of otherwise lethal ovarian cancers when coupled with depleting tumor-associated immunosuppressive dendritic cells (DCs). Here we elucidate this arousal of host responses to be due to the licensing of host DCs by co-transferred CCL5-secreting CD4⁺ T cells that recruit host antitumor immune cells. Tumor-primed CD4⁺ T cells significantly delayed tumor progression and directly activated host tumor-resident DCs which subsequently activated tumor-exposed C8⁺ T cells. These effects were long-lived, as host T cells obtained from mice treated with ACT were protective against secondary challenge with the same tumor. Disrupting CD40-CD40L interactions during ACT impaired DC maturation and ability to stimulate tumor-infiltrating CD8⁺ T cells. Similarly, abrogating CCL5 secretion reduced DC maturation and the survival increases obtained from ACT. The absence of CCL5 and CD40 further reduced the protective phenotype of the host cells against secondary challenge with the same tumor. Our data unveil a CD40-dependent mechanism of transferring immunity from adoptively transferred CCL5-secreting CD4⁺ T cells to host immune cells, causing sustained antitumor effects, and advance the field towards developing more potent anti-tumor therapies.