CCL3 augments tumor rejection and enhances CD8⁺T cell infiltration through NK and CD103⁺dendritic cell recruitment via IFNγ

Abstract

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-1α), CCL4 (MIP-1β), 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 IFNγ 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.

Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis

“…Of these genes, CCL2, which is thought to be potentially of astroglial and neuronal origin (43) and may regulate the pain response and monocyte migration during infection (44,45), has been implicated in facilitating microglial recruitment during infection (46). CCL2 upregulation may thus be an attempt to facilitate a microglial response even after microglial ablation (47). TREM2 was found to be downregulated in the brain following WNV infection in the presence of PLX5622, consistent with the fact that it is produced predominantly by microglia (48).…”

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…by activating the expression of NK cellactivatory ligands). 15,141,[334][335][336][337][338][339] Finally, most immunooncology trials do not select chemotherapeutics based on their immunostimulatory potential (which in many cases does not manifest at clinically employed dose regimens), but rather based on their use a standard-of-care for selected indications. At least in some cases, such a design precludes the activation of clinically meaningful anticancer immune responses and hence limits the clinical benefit of combinatorial regimens.…”

PD-L1 blockade enhances anti-tumor efficacy of NK cells

“…NK cells not only produce IFNγ and other cytokines, which are secreted upon recognition of the tumor, but also recruit and orchestrate responses by other immune cells such as T- and dendritic cells in the tumor bed. 7,8 (reviewed in 9,10 ) Furthermore, their direct killing of tumor cells leads to release of tumor antigens along with cytokines which likely primes the adaptive immune response for better tumor control. 11,12 …”