CD40 agonism in renal cell carcinoma enhances immune checkpoint activity through myeloid cells

Immune checkpoint blockade (ICB) has improved survival for patients with metastatic renal cell carcinoma (RCC), but there remains a need to overcome resistance mechanisms. CD40 agonists increase anti-tumoral immunity, but limited data are available on their activity in RCC. We evaluated CD40 agonism in combination with ICB in preclinical RCC models. Adding CD40 agonism to anti-CTLA-4, but not anti-PD-1, improved survival in Renca-bearing mice. CD40 agonism and anti-CTLA-4 upregulated CCL2 and increased intra-tumoral macrophages and type 1 conventional dendritic cells (cDC1), whereas polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) decreased compared with control. Neutralizing CCL2 with CD40 agonism and CTLA-4 blockade partially abrogated the anti-tumoral effect and led to less increase in cDC1 and less decrease in PMN-MDSC populations. Our studies suggest that CCL2, at least partially, mediates the anti-tumoral effects of CD40 agonism, and more importantly, that the addition of CD40 agonism to ICB, particularly anti-CTLA-4, might be beneficial in RCC.