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

Jianxin Wang, May Tun Saung, Keyu Li, Juan Fu, Kenji Fujiwara, Nan Niu, Stephen Muth, Junke Wang, Yao Xu, Noah Rozich, Haley Zlomke, Sophia Chen, Birginia Espinoza, Mackenzie Henderson, Vanessa Funes, Brian Herbst, Ding Ding, Christina Twyman Saint Victor, Qihong Zhao, Amol NarangJin He, Lei Zheng

Research output: Contribution to journalArticlepeer-review


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 (αPD-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 αPD-1 as new treatment strategies. Using PDAC mouse models, we demonstrated that RT followed by αPD-1 and prolonged treatment with CCR2/5i conferred better antitumor efficacy than other combination treatments tested. The combination of RT + αPD-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.

Original languageEnglish (US)
Article numbere20211631
JournalJournal of Experimental Medicine
Issue number5
StatePublished - May 2 2022

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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