Interleukin-10 promotes the maintenance of antitumor CD8+ T-cell effector function in situ

Abstract

Interleukin-10 (IL-10) is a multifunctional cytokine that can exert suppressive and stimulatory effects on T cells. It was investigated whether IL-10 could serve as an immunostimulant for specific CD8 ؉ cytotoxic T cell (CTL) in vivo after vaccination and, if so, under what conditions. In tumor prevention models, administration of IL-10 before, or soon after, peptide-pulsed primary dendritic cell immunization resulted in immune suppression and enhanced tumor progression. Injection of IL-10, however, just after a booster vaccine significantly enhanced antitumor immunity and vaccine efficacy. Analysis of spleen cells derived from these latter animals 3 weeks after IL-10 treatment revealed that the number of CD8 ؉ CD44 hi CD122 ؉ T cells had increased and that antigen-specific proliferation in vitro was enhanced. Although cytotoxicity assays did not support differences between the various treatment groups, 2 more sensitive assays measuring antigen-specific interferon-␥ production at the single-cell level demonstrated increases in the number of antigen-specific responder T cells in animals in the vaccine/IL-10 treatment group. Thus, IL-10 may maintain the number of antitumor CD8 ؉ T cells. In adoptive transfer studies, the ability of IL-10 to maintain CTL function could be enhanced by the depletion of CD4 ؉ T cells. This suggests that IL-10 mediates contrasting effects on both CD4 ؉ and CD8 IntroductionDendritic cells (DCs) play a key role in the initiation of CD8 ϩ cytotoxic T cell (CTL)-mediated immune responses and have been used successfully in cancer vaccines. 1,2 We have previously reported that CD8 ϩ CTLs can be generated from naive precursors using DC preloaded with leukemia antigens as stimulators. [3][4][5] Leukemic cell-derived DCs have been used to successfully treat patients with chronic myelogenous leukemia. 6 To more effectively treat patients with cancer, vaccines must not only amplify antitumor CTL responses, they must maintain them to preclude disease recurrence. The main predictor of a strong response versus a weak CTL appears to be the size of a proliferative burst. 7,8 However, for the promotion of long-term effector CTL activity, the participation of T-cell growth and antiapoptotic factors, such as interleukin 2 (IL-2), In this study, we have evaluated whether IL-10 plays a dominant role in supporting the maintenance of effector CD8 ϩ T-cell function after initial priming in situ.IL-10, which is produced by a variety of cells including T lymphocytes, B lymphocytes, and monocytes, has been identified as a key immunomodulatory cytokine 15,16 capable of mediating both immunosuppressive and immunostimulant effects. 17 In vitro studies showed that IL-10 inhibits antigen-specific activation and proliferation of human CD4 ϩ T cells, at least in part by downregulating the cytokine production (ie, IL-2 and tumor necrosis factor-␣). 18,19 IL-10 also reduces the expression of CD54 (ICAM-1), CD80, CD86, and major histocompatibility complex (MHC) class II on monocytes and DCs, resulting in incomplete T-ce...

Concurrent delivery of tumor antigens and activation signals to dendritic cells by irradiated CD40 ligand-transfected tumor cells resulted in efficient activation of specific CD8+ T cells

“…56 Alternatively, IL-10 in this setting may be stimulatory, since IL-10 was shown to promote the maintenance of tumor-specific CD8 þ T-cell effector function. 57 This is in agreement with our finding that CD8 þ T cells initially stimulated with DCs cultured with irradiated CD40L-tumor cells survived longer during the in vitro stimulation procedure. The failure of frozen/ thawed CD40L-tumor cells to induce DC maturation may be due to the denaturation of surface CD40L during the freezing/thawing treatment.…”

IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity

“…Furthermore, treatment of syngeneic mouse tumors with recombinant human IL-10 induced CD8 þ T-cell-dependent tumor rejection (33). IL-10 application was efficacious in the effector phase of tumor rejection, whereas application during tumor vaccination failed to significantly enhance tumor rejection (34).…”

Induction of antigen-specific CD4- and CD8-mediated T-cell responses by fusions of autologous dendritic cells and metastatic colorectal cancer cells

“…43 Moreover, it was also demonstrated that IL-10 production could enhance CTL generation. 44,45 In summary, we have demonstrated, using DC/CRCA fusion cells, that (i) freshly isolated metastatic CRCA cells can be used as a fusion partner, thus expanding the source of fusion cells; (ii) both CD4…”