CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma

This preclinical study showed that CCR2/CCR5 dual-antagonist counteracts radiation-induced suppressive signals in myeloid cells and upregulates the effector T cell pathway and supported the ongoing clinical trial of the combination therapy of radiation, CCR2/CCR5 dual-antagonist, and anti-PD-1 antibody for locally advanced pancreatic cancer. The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed to the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 and CCR5 were induced in PDAC following treatment with anti-PD-1 antibody (alpha PD-1); thus, we examined PDAC vaccine or radiation therapy (RT) as T cell priming mechanisms together with BMS-687681, a dual antagonist of CCR2 and CCR5 (CCR2/5i), in combination with alpha PD-1 as new treatment strategies. Using PDAC mouse models, we demonstrated that RT followed by alpha PD-1 and prolonged treatment with CCR2/5i conferred better antitumor efficacy than other combination treatments tested. The combination of RT + alpha PD-1 + CCR2/5i enhanced intratumoral effector and memory T cell infiltration but suppressed regulatory T cell, M2-like tumor-associated macrophage, and myeloid-derived suppressive cell infiltration. RNA sequencing showed that CCR2/5i partially inhibited RT-induced TLR2/4 and RAGE signaling, leading to decreased expression of immunosuppressive cytokines including CCL2/CCL5, but increased expression of effector T cell chemokines such as CCL17/CCL22. This study thus supports the clinical development of CCR2/5i in combination with RT and ICIs for PDAC treatment.

Automated summary

This preclinical study demonstrates the potential of CCR2/CCR5 dual-antagonist in counteracting radiation-induced suppressive signals and enhancing the effector T cell pathway. It supports the ongoing clinical trial of combining this therapy with radiation and anti-PD-1 antibody for locally advanced pancreatic cancer.