In vivo elimination of CD25⁺ regulatory T cells leads to tumor rejection of B16F10 melanoma, when combined with interleukin‐12 gene transfer

Abstract

CD4(+)CD25(+) T cells are an important population that plays a crucial role in the maintenance of peripheral self-tolerance. Recently, it was shown that the elimination of these cells by in vivo administration of anti-CD25 monoclonal antibody (mAb) caused the regression of highly immunogenic tumors in syngeneic mice. In this study, we examined whether B16F10 melanoma cells regressed with the elimination of CD25(+) regulatory T cells. We found the melanoma cells were not affected at all by in vivo anti-CD25 mAb administration alone but tumor rejection resulted in all mice when the administration was combined with IL-12 gene transfer to tumor cells. In vivo, depletion of natural killer (NK) cells or CD8(+) T cells cancelled the tumor rejection. NK-cell depletion allowed IL-12-transfected B16F10 melanoma (B16/IL-12) to grow from an early stage and resulted in a more rapid tumor growth of B16/IL-12 than that in mice without administration of anti-CD25 mAb. On the other hand, CD8(+) T-cell depletion did not affect the tumor growth in the early phase but allowed B16/IL-12 to grow in rather a late phase and resulted in almost the same degree of tumor growth as in mice without administration of anti-CD25 mAb. In a previous study, we showed that the elimination of CD4(+) T cells enhanced the antitumor effect of B16/IL-12 and induced vitiligo-like coat color alteration. Therefore, we also examined the frequency of the change to a vitiligo-like coat color in mice showing tumor rejection caused by CD25(+) T-cell elimination to compare with the mechanism enhancing the antitumor effects by cell elimination. The elimination of CD25(+) T cells did not induce vitiligo-like coat color changes, though that of CD4(+) T cells induced the change in 60% of mice. Furthermore, we confirmed that elimination of CD25(+) T cells did not affect the T-helper (Th) 1/Th2 cytokine profile, while that of CD4(+)T cells abrogated the Th2 cytokines (IL-4 and IL-10) and resulted in a Th1-dominant cytokine profile in the tumor-draining lymph nodes (TDLNs) of B16/IL-12-bearing mice. These results indicate that in vivo depletion of CD25(+) regulatory T cells is a potent useful adjuvant in immunotherapy of B16F10 melanoma, when combined with IL-12 gene transfer and that the enhancement of the antitumor effect by CD25(+) T-cell depletion is mediated through CD8(+) T cells and may differ from the enhancing mechanism caused by CD4(+) T-cell depletion.

Coexpression of CD40L and CD70 by semiallogenic tumor cells induces anti-tumor immunity

“…14 On the other hand, different laboratories have recently shown the involvement of CD4 þ CD25 þ regulatory T cells in B16F10 tumor tolerance and that the depletion of CD25 þ regulatory T cells further enhances the effects of immunotherapeutic treatments without increasing the incidence of autoimmunity. 15,16 Nagaı¨'s group and Prasad et al have shown that an in vivo administration of anti-CD25 antibody alone did not affect the parental tumor growth. However, when an immunotherapy protocol using cytokines or vaccination is associated with depletion of CD25 þ T regulatory cells, the antitumor effects are enhanced and syngenic immunocompetent mice thus reject the B16F10 melanoma.…”

“…Furthermore, Nagai et al have shown that CD8 þ T and NK cells are involved in B16F10 tumor rejection when antitumor treatment is associated with the depletion of CD25 þ regulatory T cells. 15 In the aim to counterattack the virulence of this murine melanoma, we have associated other strategies.…”

Responses to Human CD40 Ligand/Human Interleukin-2 Autologous Cell Vaccine in Patients with B-Cell Chronic Lymphocytic Leukemia

“…This apparent difference in outcome is difficult to interpret, because phase I studies lack the power to enable comparisons of efficacy, and measurements of T-reg cell number or function were not included in the study by Kipps et al If CD4 + /CD25 + T-reg cells can indeed compromise the generation or maintenance of antileukemic T-cell responses, their removal will be required for optimal immune stimulation by hCD40L/hIL-2 vaccines regardless of the dose or the route of administration. The availability of CD25 antibodies capable of depleting regulatory subsets in vivo should allow this notion to be tested experimentally (36,37).…”

Depleting regulatory T cells with arginine-rich, cell-penetrating, peptide-conjugated morpholino oligomer targeting FOXP3 inhibits regulatory T-cell function

“…[8][9][10][11][12] Lower levels of T reg occur in patients who are better able to control HIV and cytomegalovirus (CMV) infections. 7 Depletion of T reg in animal models 13,14 and human studies enhances tumor antigen-specific T-cell responses. 15 Similarly, in preclinical models, depletion of T reg enhances anti-viral responses.…”