Cancer Cell CCR2 Orchestrates Suppression of the Adaptive Immune Response

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2020 Jul 16

PMID 32667673

Citations 31

Authors

Miriam R Fein

Xue-Yan He

Ana S Almeida

Emilis Bruzas

Arnaud Pommier

Ran Yan

Anais Eberhardt

Douglas T Fearon

Linda Van Aelst

John Erby Wilkinson

Camila O Dos Santos

Mikala Egeblad

Affiliations

Soon will be listed here.

Abstract

C-C chemokine receptor type 2 (CCR2) is expressed on monocytes and facilitates their recruitment to tumors. Though breast cancer cells also express CCR2, its functions in these cells are unclear. We found that Ccr2 deletion in cancer cells led to reduced tumor growth and approximately twofold longer survival in an orthotopic, isograft breast cancer mouse model. Deletion of Ccr2 in cancer cells resulted in multiple alterations associated with better immune control: increased infiltration and activation of cytotoxic T lymphocytes (CTLs) and CD103+ cross-presenting dendritic cells (DCs), as well as up-regulation of MHC class I and down-regulation of checkpoint regulator PD-L1 on the cancer cells. Pharmacological or genetic targeting of CCR2 increased cancer cell sensitivity to CTLs and enabled the cancer cells to induce DC maturation toward the CD103+ subtype. Consistently, Ccr2-/- cancer cells did not induce immune suppression in Batf3-/- mice lacking CD103+ DCs. Our results establish that CCR2 signaling in cancer cells can orchestrate suppression of the immune response.

Citing Articles

Advances and prospects in tumor infiltrating lymphocyte therapy.

Qiu X, Li S, Fan T, Zhang Y, Wang B, Zhang B Discov Oncol. 2024; 15(1):630.

PMID: 39514075 PMC: 11549075. DOI: 10.1007/s12672-024-01410-5.

The power of many: Multilevel targeting of representative chemokine and metabolite GPCRs in personalized cancer therapy.

Inverso D, Tacconi C, Ranucci S, De Giovanni M Eur J Immunol. 2024; 54(12):e2350870.

PMID: 39263783 PMC: 11628915. DOI: 10.1002/eji.202350870.

CCL2 Predicts Survival in Patients with Inoperable Hepatocellular Carcinoma Undergoing Selective Internal Radiotherapy.

Haag F, Gylstorff S, Bujok J, Pech M, Relja B Cancers (Basel). 2024; 16(16).

PMID: 39199602 PMC: 11352291. DOI: 10.3390/cancers16162832.

Causal association of circulating immune cells and lymphoma: A Mendelian randomization study.

Wang F, Huang G, Luo Y, Xiong K, Liu Y, Wang Y Open Med (Wars). 2024; 19(1):20240984.

PMID: 39015296 PMC: 11249620. DOI: 10.1515/med-2024-0984.

Dynamic immune status analysis of peripheral blood mononuclear cells in patients with bloodstream infection sepsis using single-cell RNA sequencing.

Zhang S, Zhang N, Han J, Sun Z, Jiang H, Huang W Front Immunol. 2024; 15:1380211.

PMID: 38898888 PMC: 11185935. DOI: 10.3389/fimmu.2024.1380211.

References

Igney F, Krammer P . Immune escape of tumors: apoptosis resistance and tumor counterattack. J Leukoc Biol. 2002; 71(6):907-20. View

Wolf M, Hoos A, Bauer J, Boettcher S, Knust M, Weber A . Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. Cancer Cell. 2012; 22(1):91-105. DOI: 10.1016/j.ccr.2012.05.023. View

Mehta H, Malandra M, Corey S . G-CSF and GM-CSF in Neutropenia. J Immunol. 2015; 195(4):1341-9. PMC: 4741374. DOI: 10.4049/jimmunol.1500861. View

Hildner K, Edelson B, Purtha W, Diamond M, Matsushita H, Kohyama M . Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science. 2008; 322(5904):1097-100. PMC: 2756611. DOI: 10.1126/science.1164206. View

Lin E, Jones J, Li P, Zhu L, Whitney K, Muller W . Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol. 2003; 163(5):2113-26. PMC: 1892434. DOI: 10.1016/S0002-9440(10)63568-7. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Li M, Knight D, Snyder L, Smyth M, Stewart T . A role for CCL2 in both tumor progression and immunosurveillance. Oncoimmunology. 2013; 2(7):e25474. PMC: 3782157. DOI: 10.4161/onci.25474. View

Chen W, Gao Q, Han S, Pan F, Fan W . The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling. Tumour Biol. 2014; 36(2):973-81. DOI: 10.1007/s13277-014-2717-z. View

Soria G, Ben-Baruch A . The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 2008; 267(2):271-85. DOI: 10.1016/j.canlet.2008.03.018. View

10.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

11.

Spranger S, Dai D, Horton B, Gajewski T . Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell. 2017; 31(5):711-723.e4. PMC: 5650691. DOI: 10.1016/j.ccell.2017.04.003. View

12.

Winograd R, Byrne K, Evans R, Odorizzi P, Meyer A, Bajor D . Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma. Cancer Immunol Res. 2015; 3(4):399-411. PMC: 4390506. DOI: 10.1158/2326-6066.CIR-14-0215. View

13.

Nakasone E, Askautrud H, Kees T, Park J, Plaks V, Ewald A . Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell. 2012; 21(4):488-503. PMC: 3332002. DOI: 10.1016/j.ccr.2012.02.017. View

14.

Greter M, Helft J, Chow A, Hashimoto D, Mortha A, Agudo-Cantero J . GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity. 2012; 36(6):1031-46. PMC: 3498051. DOI: 10.1016/j.immuni.2012.03.027. View

15.

Dunn G, Bruce A, Ikeda H, Old L, Schreiber R . Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002; 3(11):991-8. DOI: 10.1038/ni1102-991. View

16.

Nielsen B, Lund L, Christensen I, Johnsen M, Usher P, Wulf-Andersen L . A precise and efficient stereological method for determining murine lung metastasis volumes. Am J Pathol. 2001; 158(6):1997-2003. PMC: 2216461. DOI: 10.1016/S0002-9440(10)64671-8. View

17.

Fang W, Jokar I, Zou A, Lambert D, Dendukuri P, Cheng N . CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem. 2012; 287(43):36593-608. PMC: 3476325. DOI: 10.1074/jbc.M112.365999. View

18.

Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z . GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009; 10:48. PMC: 2644678. DOI: 10.1186/1471-2105-10-48. View

19.

Hu Q, Myers M, Fang W, Yao M, Brummer G, Hawj J . Role of ALDH1A1 and HTRA2 expression in CCL2/CCR2-mediated breast cancer cell growth and invasion. Biol Open. 2019; 8(7). PMC: 6679398. DOI: 10.1242/bio.040873. View

20.

Nywening T, Wang-Gillam A, Sanford D, Belt B, Panni R, Cusworth B . Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016; 17(5):651-62. PMC: 5407285. DOI: 10.1016/S1470-2045(16)00078-4. View