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1.
PLoS One ; 16(3): e0249142, 2021.
Article in English | MEDLINE | ID: mdl-33760886

ABSTRACT

CCR2 is the major chemokine receptor that regulates appropriate trafficking of inflammatory monocytes, but the role of this chemokine receptor and its ligands during primary and secondary infection with intracellular infections remains incompletely understood. Here we used murine infection with the Live Vaccine Strain (LVS) of Francisella tularensis to evaluate the role of CCR2 during primary and secondary parenteral responses to this prototype intracellular bacterium. We find that mice deficient in CCR2 are highly compromised in their ability to survive intradermal infection with LVS, indicating the importance of this receptor during primary parenteral responses. Interestingly, this defect could not be readily attributed to the activities of the known murine CCR2 ligands MCP-1/CCL2, MCP-3/CCL7, or MCP-5/CCL12. Nonetheless, CCR2 knockout mice vaccinated by infection with low doses of LVS generated optimal T cell responses that controlled the intramacrophage replication of Francisella, and LVS-immune CCR2 knockout mice survived maximal lethal Francisella challenge. Thus, fully protective adaptive immune memory responses to this intracellular bacterium can be readily generated in the absence of CCR2.


Subject(s)
Francisella tularensis/physiology , Receptors, CCR2/genetics , Tularemia/immunology , Animals , Bacterial Vaccines/administration & dosage , Bacterial Vaccines/immunology , Chemokine CCL2/deficiency , Chemokine CCL2/genetics , Chemokine CCL2/immunology , Chemokine CCL7/deficiency , Chemokine CCL7/genetics , Chemokine CCL7/immunology , Disease Models, Animal , Disease Susceptibility , Francisella tularensis/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/cytology , Monocytes/metabolism , Receptors, CCR2/deficiency , Survival Rate , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tularemia/mortality , Tularemia/pathology , Tularemia/prevention & control , Vaccines, Attenuated/administration & dosage , Vaccines, Attenuated/immunology
2.
Nat Commun ; 11(1): 6119, 2020 11 30.
Article in English | MEDLINE | ID: mdl-33257678

ABSTRACT

The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC) largely depends on the tumor microenvironment (TME). Here, we demonstrate that CCL7 facilitates anti-PD-1 therapy for the KrasLSL-G12D/+Tp53fl/fl (KP) and the KrasLSL-G12D/+Lkb1fl/fl (KL) NSCLC mouse models by recruiting conventional DC 1 (cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression in NSCLC tumor tissues and is positively correlated with the infiltration of cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8+ and CD4+ T cells in bronchial draining lymph nodes and TME, thereby promoting tumor development in the KP mouse model. Administration of CCL7 into lungs alone or in combination with anti-PD-1 significantly inhibits tumor development and prolongs the survival of KP and KL mice. These findings suggest that CCL7 potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/immunology , Chemokine CCL7/metabolism , Chemokine CCL7/pharmacology , Immunity , Immunotherapy/methods , Lung Neoplasms/immunology , Animals , Antibodies, Monoclonal, Humanized/pharmacology , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Chemokine CCL7/deficiency , Chemokine CCL7/genetics , Chemokines/metabolism , Disease Models, Animal , Female , Genes, ras , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Tumor Microenvironment/immunology , Tumor Suppressor Protein p53
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