Abstract
Lymph node (LN) plays a critical role in tumor cell survival outside of the primary tumor sites and dictates overall clinical response in many tumor types (1, 2). Previously, we and others have demonstrated that CCL3 plays an essential role in orchestrating T cell—antigen-presenting cell (APC) encounters in the draining LN following vaccination, and such interactions enhance the magnitude of the memory T cell pool (3–5). In the current study, we investigate the cellular responses in the tumor-draining lymph nodes (TDLNs) of a CCL3-secreting CT26 colon tumor (L3TU) as compared to wild-type tumor (WTTU) during the priming phase of an antitumor response (≤10 days). In comparison to WTTU, inoculation of L3TU resulted in suppressed tumor growth, a phenomenon that is accompanied by altered in vivo inflammatory responses on several fronts. Autologous tumor-derived CCL3 (aCCL3) secretion by L3TU bolstered the recruitment of T- and B-lymphocytes, tissue-migratory CD103+ dendritic cells (DCs), and CD49b+ natural killer (NK) cells, resulting in significant increases in the differentiation and activation of multiple Interferon-gamma (IFNγ)-producing leukocytes in the TDLN. During this early phase of immune priming, NK cells constitute the major producers of IFNγ in the TDLN. CCL3 also enhances CD8+ T cell proliferation and differentiation by augmenting DC capacity to drive T cell activation in the TDLN. Our results revealed that CCL3-dependent IFNγ production and CCL3-induced DC maturation drive the priming of effective antitumor immunity in the TDLN.
Highlights
Immunogenic tumors are capable of triggering robust antitumor immune responses
IgG1a antibody was administered to NI, wild-type tumor (WTTU), and CCL3-secreting CT26 colon tumor (L3TU) cohorts as for CCL3 blockade or natural killer (NK) depletion. (C,D) Fold change of CXCL9 and CXCL10 mRNA
We aimed to distinguish the effect of CCL3 on early antitumor immune priming in the Lymph node (LN) from the later adaptive immune responses at the primary tumor site
Summary
Immunogenic tumors are capable of triggering robust antitumor immune responses. intrinsic and extrinsic factors, such as tumor cell growth rates and immune-suppressing factors, protect tumors from effective immune elimination [6]. CCL3 Enhances Lymph Node IFNγ of responding immune cells within specific contexts of the local tissue microenvironments. Secondary lymphoid organs such as lymph nodes (LNs) play an important role in the development of these mediating factors. Despite the important role LNs play in tumor progression, many of the current mechanistic insights of how immune cells respond in a tumor microenvironment (TME) come primarily from interrogations of cellular events that occur in the primary tumor sites. Studying immune interactions in the tumor draining lymph node (TDLN), not just in the primary tumor site, can provide important clues to local and global immune responses toward disseminating tumors [8, 9]
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