CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy

ABSTRACT

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

KEYWORDS:

• Immunotherapy
• MDSC
• Glioma

Acknowledgments

We would like to acknowledge Bristol Myers Squibb for providing the CCR2/CCR5 co-inhibitor BMS-687681.

Disclosure statement

M.L. has received research support from Arbor, BMS, Accuray, Tocagen, Biohaven, Kyrin-Kyowa and Biohaven, has been a consultant to Tocagen, VBI, InCephalo Therapeutics, Pyramid Bio, Merck, BMS, Insightec, Biohaven, Sanianoia, Hemispherian, Black Diamond Therapeutics, Novocure, is a shareholder of Egret Therapeutics and has patents for Focused radiation + checkpoint inhibitors, Local chemotherapy + checkpoint inhibitors and Checkpoint agonists for Neuro-Inflammation.

Data availability statement

The data that support the findings of this study stem from the pre-print: https://doi.org/10.1101/2023.03.26.534192

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2024.2338965

Additional information

Funding

This work was completed with the help of private donors who gifted Michael Lim with research funds to explore treatments for GBM. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.