Inducible CCR2+ nonclassical monocytes mediate the regression of cancer metastasis

Xianpeng Liu, Ziyou Ren, Can Tan, Félix L. Núñez-Santana, Megan E. Kelly, Yuanqing Yan, Haiying Sun, Hiam Abdala-Valencia, Wenbin Yang, Qiang Wu, Takahide Toyoda, Marija Milisav, S. Marina Casalino-Matsuda, Emilia Lecuona, Emily Jeong Cerier, Lena J. Heung, Mohamed E. Abazeed, Harris Perlman, Ruli Gao, Navdeep S. ChandelG. R.Scott Budinger, Ankit Bharat

Research output: Contribution to journalArticlepeer-review

Abstract

A major limitation of immunotherapy is the development of resistance resulting from cancer-mediated inhibition of host lymphocytes. Cancer cells release CCL2 to recruit classical monocytes expressing its receptor CCR2 for the promotion of metastasis and resistance to immunosurveillance. In the circulation, some CCR2-expressing classical monocytes lose CCR2 and differentiate into intravascular nonclassical monocytes that have anticancer properties but are unable to access extravascular tumor sites. We found that in mice and humans, an ontogenetically distinct subset of naturally underrepresented CCR2-expressing nonclassical monocytes was expanded during inflammatory states such as organ transplant and COVID-19 infection. These cells could be induced during health by treatment of classical monocytes with small-molecule activators of NOD2. The presence of CCR2 enabled these inducible nonclassical monocytes to infiltrate both intra- and extravascular metastatic sites of melanoma, lung, breast, and colon cancer in murine models, and they reversed the increased susceptibility of Nod2–/–mutant mice to cancer metastasis. Within the tumor colonies, CCR2+ nonclassical monocytes secreted CCL6 to recruit NK cells that mediated tumor regression, independent of T and B lymphocytes. Hence, pharmacological induction of CCR2+ nonclassical monocytes might be useful for immunotherapy-resistant cancers.

Original languageEnglish (US)
Article numbere179527
JournalJournal of Clinical Investigation
Volume134
Issue number22
DOIs
StatePublished - Nov 15 2024

Funding

This work was supported by NIH grants R01HL145478, R01HL147290, R01HL147575, R01HL173940, R01HL4877967, P01HL169188 (to AB), NIH P01 AG049665, and NIH P01 HL071643 (to GRSB). The Northwestern University Flow Cytometry Core Facility is supported by a Cancer Center Support Grant (NCI CA060553). We thank Chitaru Kurihara for help in collecting human blood samples. We thank Lennell Reynolds Jr. and Farida Korobova of the Northwestern University Center for Advanced Microscopy & Nikon Imaging Center for assistance in acquiring TEM data. We thank Yuliya Politanska for performing RNA-Seq. We thank Jenny Zhang and Jiao-Jing Wang of the Northwestern University Microsurgery Core of the Comprehensive Transplant Center for spleen transplantation. We thank Tim D. Sparwasser for sharing TLR7-floxed mice. We thank Ali Shilatifard, Chair of the Department of Biochemistry at Northwestern University, for critical review of the manuscript. This work was supported by NIH grants R01HL145478, R01HL147290, R01HL147575, R01HL173940, R01HL4877967, P01HL169188 (to AB), NIH P01 AG049665, and NIH P01 HL071643 (to GRSB). The Northwestern University Flow Cytometry Core Facility is supported by a Cancer Center Support Grant (NCI CA060553). We thank Chitaru Kurihara for help in collecting human blood samples. We thank Lennell Reynolds Jr. and Fari- da Korobova of the Northwestern University Center for Advanced Microscopy & Nikon Imaging Center for assistance in acquiring TEM data. We thank Yuliya Politanska for performing RNA-Seq. We thank Jenny Zhang and Jiao-Jing Wang of the Northwestern University Microsurgery Core of the Comprehensive Transplant Center for spleen transplantation. We thank Tim D. Sparwasser for sharing TLR7-floxed mice. We thank Ali Shilatifard, Chair of the Department of Biochemistry at Northwestern University, for critical review of the manuscript.

ASJC Scopus subject areas

  • General Medicine

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