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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Research Article Immunology

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 3

I-NCMs mediate the regression of melanoma metastasis.

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I-NCMs mediate the regression of melanoma metastasis. (A) Representative...
(A) Representative 2-photon images showing accumulation and colonization of B16F10-GFP in the lung at the indicated time points after retro-orbital injection into Nod2–/– mice. Scale bar: 100 μm. Dx, dextran (B) Accumulation of B16F10-LUC2 cells was detected and determined by luciferase activity using LAGO on day 3 after retro-orbital injection (d.p.i.). (C) Detection of melanoma cells in lungs in WT B6, Nr4a1–/–, and Nod2–/– mice by LAGO at the indicated dose and time points. The lung was isolated and photographed to visualize the accumulation of black dots in the metastatic B16F10-LUC2 cells after LAGO detection. (D) Metastatic B16F10 colonization in lung and other tissues was analyzed in monocyte-depleted mice. (E and F) Adoptive transfer of I-NCMs reduced metastatic colonization (E) and attenuated established metastatic B16F10 melanoma colonies (F). Approximately 1 × 105 I-NCMs from MDP-treated Nr4a1–/– mice were retro-orbitally injected into Nod2–/– mice prior to or after the injection of 3 × 105 B16F10-LUC2 cells. Colonization of B16 in the lung was determined by LAGO detection of luciferase activity. In E and F, the experimental design is shown in the upper panel; a representative image and quantification of LAGO detection of luciferase activity in B16F10-LUC2 cells in the lung are shown in the lower-left panel and lower-right panel, respectively. The data are presented as mean ± SEM; n = 3–13 in each group; *P < 0.05, **P < 0.01, ***P < 0.001; 2-tailed t test in B, E, and F; 1-way ANOVA in C.