Characterization of the CCL21-mediated melanoma-specific immune responses and in situ melanoma eradication

Abstract

Previous studies have shown that secondary lymphoid chemokine, CCL21, can be used for modulation of tumorspecific immune responses. Here, using B16F0 melanoma cells stably expressing CCL21 under the control of cytomegalovirus and ubiquitin promoters, we showed that CCL21-activated immune responses depend on the amount of melanoma-derived chemokine, which, in turn, depends on the strength of the promoter. We showed that ubiquitin promoter -driven expression of CCL21 enabled massive infiltration of tumors with CD4 + CD25 À , CD8 +

Chemokines in cancer related inflammation

“…Transfection of LIGHT, a member of the TNF superfamily, in the tumor environment induced CCL21 expression and subsequent infiltration of naive T cells which are primed locally and acquire cytotoxic functions [59]. Further, in mouse cancer models, intra-tumoral injection of CCL21 or stable transfection of antigen presenting cells lead to potent antitumor responses [60][61][62].…”

Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

“…CCL19 is the ligand for CCR7, a receptor expressed on subsets of T cells and dendritic cells (DCs) [8,9]. CCL21 is highly expressed in high endothelial venules (HEVs)-specialized vessels carrying circulating lymphocytes in and out of the lymph node-and in the T-zone of lymph nodes [10,11,12,13]. CCL21 also signals through the CCR7 receptor on natural killer (NK) cells, naϊve and memory T cells, and DCs to recruit them to developing lymph nodes and aid in their activation and function during an active immune response [10,11,12,14,15].…”

“…CCL21 is highly expressed in high endothelial venules (HEVs)-specialized vessels carrying circulating lymphocytes in and out of the lymph node-and in the T-zone of lymph nodes [10,11,12,13]. CCL21 also signals through the CCR7 receptor on natural killer (NK) cells, naϊve and memory T cells, and DCs to recruit them to developing lymph nodes and aid in their activation and function during an active immune response [10,11,12,14,15]. CXCL13 is one of the 4 most potent B cell chemoattractants known [7], causing an influx of migrating B cells as well as a subset of circulating T cells that express its cognate receptor, CXCR5 [16,17,18,19].…”

“…Another possible immune signal that may be lost during melanoma development is CCL21. Forced expression of CCL21 in melanoma cells caused an increase of NK and CD8 + T cell infiltrate resulting in a bolstered immune response when compared to melanomas lacking CCL21 [12]. …”

Recombinant DNA Technology in Emerging Modalities for Melanoma Immunotherapy

“…Addition of different cytokines and growth factors including GM-CSF, IL-2, IL12 for stimulation/support of the T cells was also tested in several studies (as exemplified in preceding paragraphs) and could be further explored. Alteration of microenvironment via application chemokines to recruit specific sets of the leukocytes to the vaccine administration site may also provide a favorable milieu for the launch of the effective DNA-vaccine induced immune response [66,67]. These and many other strategies can be proposed; however, the clinical utility of the DNA vaccination combination with other approaches remains to be determined.…”