Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy

Garrett M Dancik,James C Costello,Beth A Jirón Tamburini,Dan Theodorescu,Annie Jean,Katelyn J Hoff,Robert T Jones,Jonathan Kaye,Bogdan Czerniak,Ana Chauca-Diaz,Jason E Duex,Megan M Tu,Hany A Abdel-Hafiz

doi:10.1038/s42003-020-01441-y

Abstract

Immunotherapies targeting the PD-1/PD-L1 axis are now a mainstay in the clinical management of multiple cancer types, however, many tumors still fail to respond. CCL2 is highly expressed in various cancer types and has been shown to be associated with poor prognosis. Inhibition or blockade of the CCL2/CCR2 signaling axis has thus been an area of interest for cancer therapy. Here we show across multiple murine tumor and metastasis models that CCR2 antagonism in combination with anti-PD-1 therapy leads to sensitization and enhanced tumor response over anti-PD-1 monotherapy. We show that enhanced treatment response correlates with enhanced CD8+ T cell recruitment and activation and a concomitant decrease in CD4+ regulatory T cell. These results provide strong preclinical rationale for further clinical exploration of combining CCR2 antagonism with PD-1/PD-L1-directed immunotherapies across multiple tumor types especially given the availability of small molecule CCR2 inhibitors and antibodies.

Highlights

Immunotherapies targeting the PD-1/PD-L1 axis are a mainstay in the clinical management of multiple cancer types, many tumors still fail to respond
Complete remission and long-term disease-free survival has been reported in patients with melanoma and renal cell carcinoma following IL-2 treatment[16]
Using an in vivo functional genomics screen, we identified the DDR2 receptor tyrosine kinase as an important determinant of the efficacy of immune checkpoint blockade therapy, where inhibition in combination with PD-1-targeted antibodies leads to enhanced tumor response compared to monotherapy[21]

Summary

Introduction

Immunotherapies targeting the PD-1/PD-L1 axis are a mainstay in the clinical management of multiple cancer types, many tumors still fail to respond. We show that enhanced treatment response correlates with enhanced CD8+ T cell recruitment and activation and a concomitant decrease in CD4+ regulatory T cell These results provide strong preclinical rationale for further clinical exploration of combining CCR2 antagonism with PD-1/PD-L1-directed immunotherapies across multiple tumor types especially given the availability of small molecule CCR2 inhibitors and antibodies. While many of the patients in these trials have improved responses relative to standard of care, a significant number will not benefit from such therapies[10] This has led to a focus on identifying more effective therapeutic combinations[11,12]. Using an in vivo functional genomics screen, we identified the DDR2 receptor tyrosine kinase as an important determinant of the efficacy of immune checkpoint blockade therapy, where inhibition in combination with PD-1-targeted antibodies leads to enhanced tumor response compared to monotherapy[21]. Patel et al.[19] identified APLNR as a critical gene for enhanced response to immunotherapy, where the loss of APLNR reduced the efficacy of T cell-based immunotherapies

Methods

Results

Conclusion