Exploring the cellular and molecular mechanisms underlying the antitumor efficacy of the cytokine CCL3, Allen et al. found that tumors expressing CCL3 preferentially recruit NK cells, which contribute to increased IFNγ levels and promote DC accumulation. This leads to increased T cell infiltration, likely via DC production of CXCL9 and CXCL10. Distal administration of either recombinant CCL3 or irradiated CCL3-secreting tumor vaccine effectively halted growth of established tumors.

Inflammatory chemokines are critical contributors in attracting relevant immune cells to the tumor microenvironment and driving cellular interactions and molecular signaling cascades that dictate the ultimate outcome of host anti-tumor immune response. Therefore, rational application of chemokines in a spatial-temporal dependent manner may constitute an attractive adjuvant in immunotherapeutic approaches against cancer. Existing data suggest that the macrophage inflammatory protein (MIP)-1 family and related proteins, consisting of CCL3 (MIP-1alpha), CCL4 (MIP-1beta), and CCL5 (RANTES), can be major determinant of immune cellular infiltration in certain tumors through their direct recruitment of antigen presenting cells, including dendritic cells (DCs) to the tumor site. In this study, we examined how CCL3 in a murine colon tumor microenvironment, CT26, enhances antitumor immunity. We identified natural killer (NK) cells as a major lymphocyte subtype that is preferentially recruited to the CCL3-rich tumor site. NK cells contribute to the overall IFNgamma content, CD103(+) DC accumulation, and augment the production of chemokines CXCL9 and CXCL10 for enhanced T cell recruitment. We further demonstrate that both soluble CCL3 and CCL3-secreting irradiated tumor vaccine can effectively halt the progression of established tumors in a spatial-dependent manner. Our finding implies an important contribution of NK in the CCL3 - CD103(+) DC - CXCL9/10 signaling axis in determining tumor immune landscape within the tumor microenvironment.

Author Info: (1) Pathology, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. (2) Surgery, Case Western Reserve University School of Medicine

Author Info: (1) Pathology, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. (2) Surgery, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. (3) Pediatrics, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. (4) Pediatrics, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. (5) Pediatrics, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. (6) Pediatrics, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. (7) Pediatrics, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. (8) Pathology, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. Pediatrics, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, Ohio, United States. Angie Fowler AYA Cancer Institute, UH Rainbow Babies & Children's Hospital, Eulcid Avenue, Cleveland, Ohio, United States.

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