Inducible CCR2+ nonclassical monocytes mediate the regression of cancer metastasis
Xianpeng Liu, … , G.R. Scott Budinger, Ankit Bharat
Xianpeng Liu, … , G.R. Scott Budinger, Ankit Bharat
Published November 15, 2024
Citation Information: J Clin Invest. 2024;134(22):e179527. https://doi.org/10.1172/JCI179527.
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Inducible CCR2+ nonclassical monocytes mediate the regression of cancer metastasis

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.

Authors

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. Chandel, G.R. Scott Budinger, Ankit Bharat

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Figure 6

I-NCMs recruit NK cells to promote tumor regression.

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I-NCMs recruit NK cells to promote tumor regression. (A–E) Detection of ...
(A–E) Detection of the uptake of B10F10-GFP by I-NCMs in vitro (A–C) and in vivo (D and E). Experimental design (A) and uptake of B16F10-GFP by RFP-labeled splenic (B) or blood (C) I-NCMs at 36 hours following coculture. The GFP signal in I-NCMs was detected by flow cytometry (B) or ICC (C). Monocytes and B16 cells were cocultured at a ratio of 5:1. White and yellow scale bars: 100 and 10 μm, respectively, in C. Experimental design (D) and FACS detection of uptake of B16F10-GFP materials by monocyte subsets in blood (E, left) or lung (right) in Nr4a1–/– mice after retro-orbital injection of MDP and B16F10-GFP injection. (F–K) I-NCMs recruit NK cells through CCL6 release to sites of B16F10 melanoma metastasis. (F and G) Adoptive transfer of I-NCMs (F) and MDP treatment (G) increased NK cells in the lungs of B16F10-bearing Nod2–/– and Nr4a1–/– mice, respectively. (H) MDP-triggered attenuation of B16F10 colonization in Nr4a1–/– mice was inhibited by depletion of NK cells using NK1.1 antibody. (I) Bulk RNA-Seq data showing higher expression of Ccl6 and Ccl9, but not other detected chemokine genes, in I-NCMs. (J) Anti-CCL6 antibody reduced NK cells and (K) suppressed the MDP-mediated attenuation of B16F10 colonization in Nr4a1–/– mice. Data are presented as mean ± SEM; n = 4–10 in each group; *P < 0.05, **P < 0.01, ***P < 0.001; 2-tailed t test in F and J, Kruskal-Wallis test in H, and 1-way ANOVA in G, I, and K.