Abstract 5655: Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic cancer

Abstract

Pancreatic cancer is an aggressive malignancy with a 5 year survival rate of less than five percent. The predominant immune cells infiltrating the tumor microenvironment are monocytes/macrophages, which are reported to support tumor growth by suppressing host immune responses to the tumor. Recruitment of monocytes to various tissues, including tumors, is dependent upon activation of the chemokine receptor CCR2 by one or more of the chemokines CCL2, CCL8 and CCL13. In preclinical and clinical studies, inhibition of CCR2 in pancreatic cancer has shown to decrease tumor progression by blocking recruitment and accumulation of monocytes/macrophages in the tumor microenvironment. Analysis of human pancreatic tumors revealed elevation of both CCL2 and CSF1, which recruit monocytes, as well as the monocyte marker CD14, in advanced pancreatic cancers. Current immunotherapy using checkpoint inhibitors are effective in some tumors, but lack efficacy in immune insensitive cancers, including pancreatic cancer. Here, we report that the inhibition of CCR2 using a small molecule antagonist potentiates anti-PD-1 immunotherapy in a syngeneic, orthotropic mouse model of pancreatic cancer. Our data reveal that blocking CCR2 decreases tumor burden by blocking monocyte infiltration and creating a microenvironment more favorable for CD8 T cells activity, and provide a mechanistic rationale for investigating the combination of a CCR2 antagonist and an immune checkpoint inhibitor in pancreatic cancer. Citation Format: Christine Janson, Heiyoun Jung, Linda Ertl, Shirley Liu, Ton Dang, Yibin Zeng, Antoni Krasinski, Jeff McMahon, Penglie Zhang, Israel Charo, Rajinder Singh, Thomas J. Schall. Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5655. doi:10.1158/1538-7445.AM2017-5655

Macrophage targeting: opening new possibilities for cancer immunotherapy

“…In a mouse model of pancreatic cancer, treatment with a CCR2 antagonist decreases the infiltration of monocyte/macrophage in the tumour. In this model, CCR2 antagonist treatment in combination with anti‐PD1 antibody suppresses tumour growth, whereas single treatment with anti‐PD1 antibody is not effective . Therefore, it is likely that blockade of CCR2 signalling prevents TAM accumulation in the tumour and thereby enhances the efficacy of immune checkpoint inhibition.…”

“…In this model, CCR2 antagonist treatment in combination with anti-PD1 antibody suppresses tumour growth, whereas single treatment with anti-PD1 antibody is not effective. 39 Therefore, it is likely that blockade of CCR2 signalling prevents TAM accumulation in the tumour and thereby enhances the efficacy of immune checkpoint inhibition. Treatment with CSF1R antagonists (e.g.…”

Targeting Macrophage-Recruiting Chemokines as a Novel Therapeutic Strategy to Prevent the Progression of Solid Tumors

“…In line with this notion, the combined treatment with a CCR1 antagonist and anti-PDL1 antibody significantly reduces tumor burden compared to either of single treatments in a mouse model of breast cancer ( 124 ). It is also reported that treatment with a CCR2 antagonist in combination with anti-PD1 antibody suppresses tumor growth in a mouse model of pancreatic cancer, whereas single treatment with anti-PD1 antibody is not effective ( 125 ). These pre-clinical data suggest that blockade of macrophage-recruiting chemokine receptors combined with immunotherapy is an attractive approach.…”

Cancer-Associated Fibroblasts: Accomplices in the Tumor Immune Evasion

“…However, no objective responses were observed with CCR2-CCL2 inhibitors when administrated as monotherapy in metastatic castration-resistant prostate cancer [ 160 ] or in combination chemotherapy in pancreatic cancer [ 161 , 162 ]. Despite these disappointing results, murine models showed that the CCR2-CCL2 axis blockade may potentiate ICI efficacy [ 163 ] leading to exploration of the combination with nivolumab (anti-PD1) in early phase trials in several cancer types (NCT03496662, NCT03767582, NCT03184870, NCT04123379). Furthermore, CXCL12-CXCR4 signaling is involved in stromal-immune crosstalk [ 164 ] giving a rationale for the clinical investigation of CXCR4 inhibitors in combination with anti-PD1 in metastatic pancreatic (NCT04177810, NCT02826486) and head and neck cancers (NCT04058145).…”