CCL3 augment antitumor immune priming in the tumor draining lymph node
JOURNAL OF IMMUNOLOGY(2017)
Abstract
Abstract Lymph nodes (LNs) represent an area of interest for targeting metastatic tumors because they play an essential role in tumor survival in non-native tissues. The chemokine CCL3 is important in recruiting first-responder immune cells to areas of epithelial insult and orchestrating cellular contacts in the LNs of vaccinated mice that subsequently lead toward the enhancement of memory CD8+ T cell generation. We hypothesize that by introducing a continuous supply of CCL3 into the microenvironment of a metastatic tumor, we can redirect a LN destined for tumor-tolerance toward the production of greater antitumor cellular responses. To interrogate our hypothesis, we subcutaneously inoculated naïve murine recipients with a Balb/c colon metastatic tumor (CT26) that is either the wild-type (WTTUs) or WTTUs transfected to secrete CCL3 (L3TUs). Immunocompetent mice injected with L3TUs resulted in a suppression of tumor growth compared to the WTTU. In vivo analysis across 7-days post-tumor injections with WTTUs or L3TUs, revealed an enhanced accumulation of endogenous DCs, NKs, and lymphocytes in the TDLNs. In vitro analysis showed that OVA-peptide or whole-protein-pulsed bone marrow derived dendritic cells (BMDCs) cultured with CCL3, showed an enhanced capacity to induce proliferation of antigen-specific T cells. Examination of the day-5 TDLNs for direct signs of adaptive antitumor responses also revealed an enhanced production of the antitumor cytokine, IFNγ compared to WTTUs and the specific recruitment of antitumor-associated DCs to the TDLN.
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