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.
View: Text | PDF
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

×

Figure 1

Ontogenetic dichotomy of I-NCMs and N-NCMs.

Options: View larger image (or click on image) Download as PowerPoint
Ontogenetic dichotomy of I-NCMs and N-NCMs. (A–C) NOD2 activation in viv...
(A–C) NOD2 activation in vivo by MDP but not isomer control induced conversion of blood CMs in WT and Nr4a1–/–, but not Nod2–/– or double-mutant Nr4a1–/– Nod2–/–, mice to I-NCMs (A), in a dose- (B) and time-dependent (C) manner. (D and E) Inhibition of the NOTCH2 signaling pathway by either gliotoxin (10 mg/kg) or DAPT (25 mg/kg) did not impair the development of I-NCMs in Nr4a1–/– mice but reduced N-NCMs in Nod2–/– mice. (F and G) Development of I-NCMs was not altered by conditional genetic depletion of TLR7 in CCR2+ CM or TLR7/8 activation by R848 treatment (50 μg/mouse). (H–L) Four weeks after splenectomy or sham surgery, mice were treated with MDP or control for 36 hours, and the monocyte subsets were analyzed by flow cytometry. (H–J) The increase in I-NCMs in the bone marrow (H), blood (I), and lung (J) was not impaired by splenectomy (Splx) in Nr4a1–/– mice. Interstitial macrophages (IMs); monocyte-derived dendritic cells (MoDCs). (K) The ratio of LY6Clo NCMs in blood monocytes was stabilized 2 weeks after splenectomy in the blood of WT B6 mice. n = 5. (L) Ratio of monocyte subsets in total monocytes in BM, blood, and lung in Nod2–/– mice (n = 3–4). Unless otherwise mentioned, MDP treatment indicates 1–2 doses of 10 mg/kg MDP via retro-orbital injection for 36 hours; n = 3–12 mice in each group; data are presented as mean ± SEM. *P < 0.05; **P < 0.01, ***P < 0.001; 2-tailed t test was used for A, F, and G; Kruskal-Wallis (nonparametric) test for C: IntM and NCM, J: NCM, and K: IntM; 1-way ANOVA for the rest of the panels.