Agonistic CD40 elicits CD8+ T-cell-dependent primary responses and CD4+ T-cell-dependent long-term immunity in breast cancer.

There has been marked improvement in the clinical outcome of triple-negative breast cancer (TNBC) with the use of immune checkpoint blockade (ICB) although serious immune-related adverse effects are not uncommon. However, other subtypes including luminal ER+ and HER2+ breast cancers are largely unresponsive to ICB. Approximately 35% of TNBCs also do not fully respond to ICB. Here we hypothesize that improving priming by cross-presenting conventional dendritic cells (cDCs) with an agonistic CD40 antibody (aCD40) may be complementary to ICB. Systemic administration of aCD40 induced T cell proliferation and activation in tumor-draining lymph nodes and attracted effector T cells to the tumor bed from the periphery. This effect was largely due to activation and maturation of type 1 conventional dendritic cells (cDC1s). aCD40 alone slowed tumor growth and its combination with ICB cured tumor-bearing mice, accomplishing a "vaccine effect" and the immune-mediated rejection of tumor rechallenge. The anti-tumor effect of aCD40 was cDC1 and CD8 + T cell-dependent, whereas the rejection of secondary tumor rechallenge in cured mice required CD4 + T cells. Importantly, intra-tumoral administration of aCD40 combined with systemic or intra-tumoral ICB-to mimic neoadjuvant therapeutic approaches-induced complete regressions of both treated and distant tumors. These findings demonstrate aCD40 efficacy in preclinical models of breast cancer and further supports intra-tumoral administration of both aCD40 and ICB as an effective treatment that might limit systemic exposure and lower risk of immune-related toxicity.