Synergistic antitumor effect by coexpression of chemokine CCL21/SLC and costimulatory molecule LIGHT

Abstract

To establish a more efficient treatment for immunotherapy against solid tumors, we have evaluated the antitumor effect by coexpression of a chemokine CCL21/secondary lymphoid tissue chemokine and a costimulatory molecule LIGHT in colon carcinoma C26. C26 cells expressing either CCL21 or LIGHT exhibited a significantly reduced tumor growth in vivo, and mice inoculated with these cells showed a prolonged survival, but eventually all these mice died. In contrast, C26 cells expressing both CCL21 and LIGHT exhibited a minimal tumor growth in vivo, and all these mice survived healthily with a tumor remission and consequently acquired a strong protective immunity. A markedly increased infiltration of mature dendritic cells (DCs), and CD8 þ T cells was observed in the tumor mass, and their spleen cells showed a greatly enhanced cytotoxic T lymphocyte (CTL) activity against C26 tumor and interferon (IFN)-g production. Neutralization of IFN-g or depletion of CD8 þ or CD4 þ T cells significantly reduced the antitumor activity. These results suggest that the combined treatment with CCL21 and LIGHT is able to induce a synergistic antitumor effect to eradicate tumor completely by greatly enhancing tumor-infiltration of lymphocytes including mature DCs and CD8 þ T cells, resulting in markedly augmented CTL activity and IFN-g production.

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

“…The involvement of T lymphocytes in CCL21-mediated tumor targeting has previously been shown (4,5). However, in contrast to previous findings, when B16F0-UB-CCL21 cells were used for tumor inoculation, melanomas were heavily infiltrated with CD4 + CD25…”

“…It has thus been suggested that this chemokine may promote recruitment of APC and T lymphocytes to a tumor mass to facilitate antigen recognition and enhance tumorspecific immune responses. In support of this concept, it was recently shown that the presence of CCL21 in the vicinity of a tumor induces infiltration of tumors with dendritic cell and CD8 + T cell and leads to immunemediated inhibition of melanoma (3), lung (4), and colon (5) carcinomas in experimental animals. Splenocytes isolated from these CCL21-treated mice showed greatly enhanced CTL activity against tumor cells (5).…”

“…In support of this concept, it was recently shown that the presence of CCL21 in the vicinity of a tumor induces infiltration of tumors with dendritic cell and CD8 + T cell and leads to immunemediated inhibition of melanoma (3), lung (4), and colon (5) carcinomas in experimental animals. Splenocytes isolated from these CCL21-treated mice showed greatly enhanced CTL activity against tumor cells (5). The chemoattractive properties of CCL21 were also used in the development of the dendritic cell -based vaccines.…”

Adenovirus-mediated LIGHT gene modification in murine B-cell lymphoma elicits a potent antitumor effect

“…They reasoned that the observed enhancement in CTL activity and IFN-c production was mainly due to the efficient infiltration of the tumor by these immune cells. 32 Previous findings have also demonstrated that in situ expression of LIGHT could promote increased infiltration by CD8…”

Enhancement of DNA vaccine potency by sandwiching antigen-coding gene between secondary lymphoid tissue chemokine (SLC) and IgG Fc fragment genes

“…Tumor volumes were calculated according to the formula: tumor volume = 0.5 (width 2 x length). 23 For the in vivo tumor treatment experiments using a lung metastasis model, mice (eight mice per group) were challenged with 1 x 10 5 TC-1 cells/mouse via tail vein (day 0). On day 7, mice were vaccinated with 1.25 µg of pSLC-E7-Fc, pE7-Fc and pCMV respectively and killed on day 21.…”