Using an orthotopic, isograft breast cancer mouse model, Fein and He et al. showed that Ccr2 deletion from tumor cells reduced tumor growth and promoted host survival. Gene expression profiles of antigen processing and immune-mediated cell killing were enriched in Ccr2-/- tumor cells. PD-1+CD107a+CD8+ T cells and CD86+CD103+ DCs, but few granulocytic MDSCs, infiltrated Ccr2-/- tumors. Ccr2+/+ cancer cell-derived tumor growth rates were unaltered by Ccr2+/+ or -/- cancer cell contralateral mammary gland grafts. Ccr2-/- and +/+ cancer cell-derived tumors grew comparably in T cell-deficient and Batf3-/- mice, evidencing CCR2-mediated adaptive/innate immune crosstalk.
Contributed by Paula Hochman
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.
Author Info: (1) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Graduate Program in Genetics, Stony Brook University, Stony Brook, NY. (2) Cold Spring Harbor Laboratory, Cold Spring Har
Author Info: (1) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Graduate Program in Genetics, Stony Brook University, Stony Brook, NY. (2) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. (3) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. (4) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Watson School of Biological Sciences, Cold Spring Harbor, NY. (5) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. (6) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Watson School of Biological Sciences, Cold Spring Harbor, NY. (7) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Departement de Biologie, Ecole Normale Superieure de Lyon, Lyon, France. (8) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK. Weill Cornell Medical College, New York, NY. (9) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. (10) Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI. (11) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. (12) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
