1. CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma.
- Author
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Wang J, Saung MT, Li K, Fu J, Fujiwara K, Niu N, Muth S, Wang J, Xu Y, Rozich N, Zlomke H, Chen S, Espinoza B, Henderson M, Funes V, Herbst B, Ding D, Twyman-Saint Victor C, Zhao Q, Narang A, He J, and Zheng L more...
- Subjects
- Animals, Mice, Receptors, CCR5, Tumor Microenvironment, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, CCR5 Receptor Antagonists pharmacology, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal radiotherapy, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms radiotherapy, Receptors, CCR2 antagonists & inhibitors
- Abstract
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., (© 2022 Wang et al.) more...
- Published
- 2022
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