Immune responses in the draining lymph nodes against cancer: Implications for immunotherapy

Abstract

Regional lymph nodes are the first site for melanoma metastases. The sentinel node (SN), on the direct lymphatic drainage pathway, which usually harbors first metastases, demonstrates significant suppression in its ability to respond to antigenic stimulation. This down-regulation of SN immunity is likely the basis of its susceptibility to tumor metastases, suggesting a potential role of the immune system in the control of malignant tumors. Despite immune dysfunction in the SN, phase II trials of systemic post-operative immunotherapy with a polyvalent melanoma vaccine developed at the John Wayne Cancer Institute showed improved 5-year overall survival in patients with melanoma metastatic to regional nodes. However, most immunotherapy clinical trials have failed to demonstrate a significant clinical response, and analyses of immune responses to tumor-associated antigens that correlate clinical responses have not been established. Therefore, refinements in assay methodologies and improvements in vaccine designs are critical to the success of cancer immunotherapy. Antigen presentation by dendritic cells (DCs) is the most potent means to initiate a T cell immunity. Dendritic cell-based immunotherapies have been vigorously attempted in the past decade. To improve the immunogenicity of cancer vaccines, we recently generated heterokaryons of DCs and tumor cells by electrofusion. The fusion hybrids retained their full antigen-presenting capacity and all natural tumor antigens. In pre-clinical animal experiments, a single injection of the DC-tumor fusion hybrids was sufficient to mediate the regression of tumors established in the lung, skin and brain. Most interestingly, successful therapy required the delivery of fusion hybrids directly into lymphoid organs such as lymph nodes. A clinical trial is now being carried out to test the immunogenicity and therapeutic effects of fusion hybrids for the treatment of metastatic melanoma.

Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients

“…22). However, most immunotherapy trials have met with limited success, failing to demonstrate significant clinical responses (22,23). It is believed that combination immunotherapy such as adoptive transfer of in vitro primed T cells and subsequent vaccination may foster enhanced memory T cell responses (24,25).…”

Long-Term Protective Effect of Mature DC-LAMP+ Dendritic Cell Accumulation in Sentinel Lymph Nodes Containing Micrometastatic Melanoma

“…However, to the best of our knowledge, this study is the first to have correlated mature DCs in the SLN with overall survival. In melanomas, it was suggested that invasion of lymph nodes by tumor cells results in suppression of lymph node functions with alterations in immune cell ratio and activity (20,25,33). Cochran et al reported that the paracortex of lymph nodes with melanoma metastases contained decreased numbers of DCs (33,34) that were phenotypically less mature as compared with DCs in nonmetastatic lymph nodes (33).…”

Cancer-Induced Signaling Defects in Antitumor T Cells

“…Finally, there have been reports that TCRζ levels are not sig-nificantly reduced in either PBL or TIL in renal cell carcinoma (Cardi et al, 1997) or in TIL (in frozen thin sections) in Hodgkin's disease (Dukers et al, 2000) arguing against this notion. Despite the concerns that these data illustrate in consideration of the biochemical basis of systemic Tcell dysfunction caused by tumor growth, tumor-induced defective antitumor-specific immune response is probably common in cancer and is causally related to tumor escape from immune response Shu et al, 2006).…”