Background The resistance of pancreatic ductal adenocarcinoma(PDAC) to immune checkpoint inhibitors(ICIs) is mainly attributed to the immune-quiescent nature of its tumor microenvironment(TME). Radiotherapy(RT) activates innate responses including the RAGE and TLR2/4 pathways and subsequently modifies the TME by promoting the release of chemokines that recruit inflammatory cells into the TME. In this preclinical study, we examined the PDAC vaccine or RT as a T-cell priming mechanism together with BMS-687681, a small molecule dual-antagonist of CCR2 and CCR5(CCR2/5i) as an immunosuppressive TME-targeting agent, in combination with the anti-PD-1 antibody(αPD-1) as a new treatment.
Materials and Methods The hemi-spleen and Orthotopic mice model were used to investigate both GVAX and RT as T-cell priming agents in combination regimens that included αPD-1 and CCR2/5i. Dissected orthotopic pancreatic tumors were collected for analysis of tumor-infiltrating immune cells by flow cytometry. RNA from tumor-infiltrating immune cell pellets and whole-exome RNA sequencing was performed for further mechanism research.
Results CCR2 and CCR5 are associated with the immunosuppressive TME of PDAC patients and their expression were induced after treatment with GVAX+nivolumab. Using a mouse model of PDAC, we demonstrated that the addition of GVAX to CCR2/5i+αPD-1 combination therapy did not significantly improve antitumor activity. However, RT followed by αPD-1 and prolonged treatment with CCR2/5i conferred significantly better antitumor efficacy compared to the other combination treatments we studied. The combination of RT, αPD-1, and CCR2/5i enhanced intratumoral effector and memory T-cell infiltration. This combination suppressed Treg, M2-like TAM, and M-MDSC infiltration, but not M1-like TAM and PMN-MDSC infiltration. Finally, RNA sequencing showed that CCR2/5i partially inhibited RT-induced TLR2/4&RAGE signaling, which would have otherwise led to the release of immunosuppressive cytokines including CCL2 and CCL5. The inhibition of TLR2/4&RAGE signaling permitted the expression of effector T-cell chemokines such as CCL17 and CCL22.
Conclusions This study thus supports the clinical development of CCR2/5i in combination with RT and ICIs for PDAC treatment.
Disclosure Information J. Wang: None. M. Tun Saung: None. K. Fujiwara: None. N. Niu: None. A. Narang: None. J. He: None. L. Zheng: None.
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