Synergistic antitumor activity by dual blockade of CCR1 and CXCR2 expressed on myeloid cells within the tumor microenvironment

Hideyuki Masui; Kenji Kawada; Yoshiro Itatani; Hideyo Hirai; Yuki Nakanishi; Yoshiyuki Kiyasu; Keita Hanada; Michio Okamoto; Wataru Hirata; Yasuyo Nishikawa; Naoko Sugimoto; Takuya Tamura; Yoshiharu Sakai; Kazutaka Obama

doi:10.1038/s41416-024-02710-x

Synergistic antitumor activity by dual blockade of CCR1 and CXCR2 expressed on myeloid cells within the tumor microenvironment

Br J Cancer. 2024 May 15. doi: 10.1038/s41416-024-02710-x. Online ahead of print.

Authors

Hideyuki Masui¹, Kenji Kawada^{2

3}, Yoshiro Itatani¹, Hideyo Hirai⁴, Yuki Nakanishi⁵, Yoshiyuki Kiyasu^{1

6}, Keita Hanada^{1

7}, Michio Okamoto^{1

8}, Wataru Hirata¹, Yasuyo Nishikawa¹, Naoko Sugimoto¹, Takuya Tamura¹, Yoshiharu Sakai^{1

9}, Kazutaka Obama¹

Affiliations

¹ Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. kkawada@kuhp.kyoto-u.ac.jp.
³ Department of Surgery, Kurashiki Central Hospital, Okayama, Japan. kkawada@kuhp.kyoto-u.ac.jp.
⁴ Laboratory of Stem Cell Regulation, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
⁵ Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁶ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Surgery, Rakuwakai Otowa Hospital, Kyoto, Japan.
⁸ Department of Surgery, Uji-Tokushukai Medical Center, Kyoto, Japan.
⁹ Department of Surgery, Japanese Red Cross Osaka Hospital, Osaka, Japan.

PMID: 38750114
DOI: 10.1038/s41416-024-02710-x

Abstract

Background: Chemokine signaling within the tumor microenvironment can promote tumor progression. Although CCR1 and CXCR2 on myeloid cells could be involved in tumor progression, it remains elusive what effect would be observed if both of those are blocked.

Methods: We employed two syngeneic colorectal cancer mouse models: a transplanted tumor model and a liver metastasis model. We generated double-knockout mice for CCR1 and CXCR2, and performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type, Ccr1^-/-, Cxcr2^-/- or Ccr1^-/-Cxcr2^-/- mice.

Results: Myeloid cells that express MMP2, MMP9 and VEGF were accumulated around both types of tumors through CCR1- and CXCR2-mediated pathways. Mice reconstituted with Ccr1^-/-Cxcr2^-/- BM exhibited the strongest suppression of tumor growth and liver metastasis compared with other three groups. Depletion of CCR1⁺CXCR2⁺ myeloid cells led to a higher frequency of CD8⁺ T cells, whereas the numbers of Ly6G⁺ neutrophils, FOXP3⁺ Treg cells and CD31⁺ endothelial cells were significantly decreased. Furthermore, treatment with a neutralizing anti-CCR1 mAb to mice reconstituted with Cxcr2^-/- BM significantly suppressed tumor growth and liver metastasis.

Conclusion: Dual blockade of CCR1 and CXCR2 pathways in myeloid cells could be an effective therapy against colorectal cancer.