Cancer cell CCR2 orchestrates suppression of the adaptive immune response

Fein, M. R.; He, X. Y. R.; Almeida, A. S.; Bruzas, E. S.; Pommier, A.; Eberhardt, A.; Fearon, D. T.; Wilkinson, J. E.; dos Santos, C. O.; Egeblad, M.

doi:10.1101/390187

bioRxiv · 10.1101/390187

Cancer cell CCR2 orchestrates suppression of the adaptive immune response

Fein, M. R.·He, X. Y. R.·Almeida, A. S.·Bruzas, E. S.·Pommier, A.·Eberhardt, A.·Fearon, D. T.·Wilkinson, J. E.·dos Santos, C. O.·Egeblad, M.

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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 [~]2-fold 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 upregulation of MHC class I and downregulation 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. SummaryC-C chemokine receptor type 2 (CCR2) expressed on monocytes facilitates their recruitment to tumors. Here, CCR2 signaling in cancer cells is shown to suppress immune control of tumors, in part by reducing CD103+ dendritic cell recruitment.

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Fein, M. R., He, X. Y. R., Almeida, A. S., Bruzas, E. S., Pommier, A., Eberhardt, A., Fearon, D. T., Wilkinson, J. E., dos Santos, C. O., Egeblad, M.. 2018-08-13. Cancer cell CCR2 orchestrates suppression of the adaptive immune response. https://doi.org/10.1101/390187

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