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.
Subject(s)
Adaptive Immunity/immunology , Immune Tolerance , Mammary Neoplasms, Experimental/immunology , Receptors, CCR2/physiology , Adaptive Immunity/physiology , Animals , Apoptosis , B7-H1 Antigen/metabolism , Dendritic Cells/immunology , Dendritic Cells/physiology , Female , Histocompatibility Antigens Class I/metabolism , Immune Tolerance/immunology , Immune Tolerance/physiology , Interferons/metabolism , Mice , Mice, Inbred C57BL , Receptors, CCR2/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/physiologyABSTRACT
Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to awaken, resume proliferating, and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer. Mechanistic analysis revealed that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin α3ß1 signaling. Antibodies against NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at preventing dormant cell awakening could potentially prolong the survival of cancer patients.
Subject(s)
Carcinogenesis/metabolism , Extracellular Traps/enzymology , Lamins/metabolism , Lung Neoplasms/pathology , Neutrophils/enzymology , Pneumonia/pathology , Animals , DNA/metabolism , Humans , Inflammation/chemically induced , Inflammation/microbiology , Integrin alpha3beta1/metabolism , Leukocyte Elastase/metabolism , Lipopolysaccharides , Lung/pathology , MCF-7 Cells , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred BALB C , Neoplasms, Experimental/pathology , Pneumonia/chemically induced , Pneumonia/microbiology , Pneumonia, Bacterial/etiology , Pneumonia, Bacterial/pathology , Protein-Arginine Deiminase Type 4 , Protein-Arginine Deiminases/antagonists & inhibitors , Protein-Arginine Deiminases/metabolism , Proteolysis , Rats , Signal Transduction , Smoking , NicotianaABSTRACT
Cancer cells can directly stimulate the generation and recruitment of tumor-supportive bone marrow-derived cells (BMDCs), including neutrophils, via secreted factors. A new study demonstrates that lung tumors also remotely activate bone-residing osteoblasts, which in turn promote neutrophil production. This is a multistep mechanism of establishing a supportive tumor microenvironment.
