CCL3 Enhances Antitumor Immune Priming in the Lymph Node via IFNγ with Dependency on Natural Killer Cells

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.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…In a tumor, an active immune response results in the production of CCL3 and CCL4 by B cells [ 116 ] and basophils [ 117 ]. The produced chemokines act as chemoattractants for anti-cancer TIL with CCR1 and CCR5 [ 115 , 118 , 119 , 120 , 121 ]. However, in a tumor both CCL3 and CCL4 may be cleaved by cathepsin D [ 122 ] and chemokine decoy receptor ACKR2/D6 [ 2 , 123 ], which suppresses the anti-cancer effect of these two CC chemokines.…”

Applications of chemokines as adjuvants for vaccine immunotherapy

“…In these studies, antigenic delivery with chemokines such as CCL3 have resulted in enhanced immunogenicity and protection against these pathogens. The chemokine CCL3 has demonstrated the ability to attract natural killer (NK) and CD8+ T cells, and has been investigated as an adjuvant for effective vaccines [26].…”

Cancer/testis Antigen MAGEA3 Interacts with STAT1 and Remodels the Tumor Microenvironment

“…Moreover, the function of STAT1 in regulation of innate and adaptive immune responses in tumor microenvironment (TME) has been best described, for example, STAT1 regulates the expression of major histocompatibility complex I (MHC class I) molecules on the surface of tumor cells which present antigens to CD8+ T cells for recognition 27; STAT1 promotes polarization of macrophages into M1 type by modulating cytokines expression 28. In addition, it has been reported that many chemokines are target genes of STAT1, such as CCL3, CCL5, CXCL1, CXCL10 and CXCL11, which play important roles in recruiting immune cells into TME 29-32. As different immune cell subsets have distinct effects on tumor progression and therapeutic outcomes, thus STAT1 acts as an important regulator of anti-tumor response in TME.…”

“…It was reported that CXCL10 and CXCL11 can recruit CTLs, Th1 and NK cells into TME by binding to their receptors CXCR3 and develop effective tumor suppression; CXCL1, CCL3 and CCL5 were reported to recruit neutrophils and macrophages to tumor tissues by binding to their corresponding receptors CXCR2, CCR1, CCR3 and CCR5 12. The contributions of CXCL1, CCL3 and CCL5 to anti-tumor immunity in TME are complex, and whether they function as a positively or a negatively regulator in immune responses should depend on the context and occurred on multiple levels 29, 34-37.…”