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 inhibition 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 the CD103+ DC subtype. Our results establish that CCR2 signaling in cancer cells can orchestrate suppression of the immune response.
Summary C-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 large part by enabling cancer cells to inhibit CD103+ dendritic cell recruitment.
Abbreviations
- BMDC
- bone marrow-derived dendritic
- cells CCL2
- C-C chemokine ligand 2
- CCR2
- C-C chemokine receptor type 2
- chOVA
- mCherry-ovalbumin
- CTL
- cytotoxic T lymphocyte
- DC
- dendritic cell
- dLN
- draining lymph node
- G-CSF
- granulocyte colony-stimulating factor
- GM-CSF
- granulocyte-macrophage colony-stimulating factor
- IACUC
- Institutional Animal Care and Use Committee
- IFN-γ
- interferon gamma
- LAMP-1
- lysosomal-associated membrane protein 1
- MDSC
- myeloid-derived suppressor cell
- MHC
- major histocompatibility complex
- MMTV
- mouse mammary tumor virus
- PD-L1
- programmed cell death ligand 1
- PFA
- paraformaldehyde
- PyMT
- polyoma middle T
- RPKM
- reads per kilobase million
- RPMI
- Roswell Park Memorial Institute
- TCGA
- The Cancer Genome Atlas
- TCR
- T cell receptor
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick end labeling