Cutting Edge: IL-10-Producing CD4+ T Cells Mediate Tumor Rejection

Segal, Benjamin M.; Glass, Deborah D.; Shevach, Ethan M.

doi:10.4049/jimmunol.168.1.1

Cited by 71 publications

(48 citation statements)

References 32 publications

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“…Both CD4 ϩ and CD8 ϩ T cells have been described to be important for the induction of tumor regression and the development of protective immunity (17,18,37,38). At first glance, the finding that CD8 ϩ , but not CD4 ϩ , T cells are required for the anti-tumor response of IL-21 is not in agreement with the doctrine that CD4 ϩ T helper cells are required for activation of naive CD8 ϩ T cells (39).…”

Section: Discussioncontrasting

confidence: 43%

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

Ma¹,

Whitters²,

Konz³

et al. 2003

The Journal of Immunology

162

148

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IL-21 is a key factor in the transition between innate and adaptive immune responses. We have used the cytokine gene therapy approach to study the antitumor responses mediated by IL-21 in the B16F1 melanoma and MethA fibrosarcoma tumor models in mice. Retrovirally transduced tumor cells secreting biologically functional IL-21 have growth patterns in vitro similar to that of control green fluorescent protein-transduced cells, but are completely rejected in vivo. We show that IL-21 activates NK and CD8+ T cells in vivo, thus mediating complete rejection of poorly immunogenic tumors. Rejection of IL-21-secreting tumors requires the presence of cognate IL-21R and does not depend on CD4+ T cell help. Interestingly, perforin, but not IFN-γ or other major Th1 and Th2 cytokines (IL-12, IL-4, or IL-10), is required for the IL-21-mediated antitumor response. Moreover, IL-21 results in 50% protection and 70% cure of nonimmunogenic tumors when given before and after tumor challenge, respectively, in C57BL/6 mice. We conclude that IL-21 immunotherapy warrants clinical evaluation as a potential treatment for cancer.

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Section: Discussioncontrasting

confidence: 43%

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

Ma¹,

Whitters²,

Konz³

et al. 2003

The Journal of Immunology

162

148

View full text Add to dashboard Cite

show abstract

“…For instance, tumor-infiltrating cells such as eosinophils and macrophages contribute to an effective antitumor response after activation by neighboring tumor-specific CD4 ϩ T cells (29)(30)(31)(32). We showed that vaccine-induced CD4 ϩ T cells were capable of producing the cytolytic molecule perforin and, accordingly, may have an immediate effector function against tumors, as has been shown in vitro (33,34) and in vivo (35). Finally, IFN-␥ secreted by tumor-infiltrating CD4 ϩ T cells or activated bystander cells has the potential to promote tumor recognition and elimination by up-regulating expression of MHC molecules and might also contribute to the inhibition of tumor angiogenesis (36,37).…”

Section: Discussionmentioning

confidence: 96%

Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming

Atanackovic

Altorki

Cao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

144

107

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We previously reported results of a phase II trial in which recombinant MAGE-A3 protein was administered with or without adjuvant AS02B to 18 non-small-cell lung cancer (NSCLC) patients after tumor resection. We found that the presence of adjuvant was essential for the development of humoral and cellular responses against selected MAGE-A3 epitopes. In our current study, 14 patients that still had no evidence of disease up to 3 years after vaccination with MAGE-A3 protein with or without adjuvant received an additional four doses of MAGE-A3 protein with adjuvant AS02B. After just one boost injection, six of seven patients originally vaccinated with MAGE-A3 protein plus adjuvant reached again their peak antibody titers against MAGE-A3 attained during the first vaccination. All seven patients subsequently developed even stronger antibody responses. Furthermore, booster vaccination widened the spectrum of CD4 ϩ and CD8 ؉ T cells against various new and known MAGE-A3 epitopes. In contrast, only two of seven patients originally vaccinated with MAGE-A3 protein alone developed high-titer antibodies to MAGE-A3, and all these patients showed very limited CD4 ؉ and no CD8 ؉ T cell reactivity, despite now receiving antigen in the presence of adjuvant. Our results underscore the importance of appropriate antigen priming using an adjuvant for generating persistent B and T cell memory and allowing typical booster responses with reimmunization. In contrast, absence of adjuvant at priming compromises further immunization attempts. These data provide an immunological rationale for vaccine design in light of recently reported favorable clinical responses in NSCLC patients after vaccination with MAGE-A3 protein plus adjuvant AS02B.antibody ͉ CD4 ϩ T cell ͉ CD8 ϩ T cell ͉ immunization ͉ non-small-cell lung cancer

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“…Recent work (Segal et al, 2002) demonstrated that IL-10 producing CD4+ T cells can manifest anti-tumor functions. The IL-10 maintains the number of anti-tumor CD8+ T cells.…”

Section: Discussionmentioning

confidence: 99%

Influence of age, castration, and testosterone on T cell subsets in healthy and leukemia grafted mice

Aboudkhil¹,

Zaîd

Henry³

et al. 2003

Biology of the Cell

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The distribution of T cell subsets in pubertal (2 months) and post-pubertal (10 months) mice showed a significant decrease in the percentage of CD4+ splenocytes and peripheral blood lymphocytes (PBL) with age, unlike the percentage of CD8+ cells in PBL, which remained unchanged. The change in the distribution of T cell subsets in the spleen and blood occurred in 2 months old castrated mice, as in 10 months old animals. P388 tumor grew better in post-pubertal and in castrated mice than in young mice. The intact mice survived longer than the castrated ones. The relative number of CD4+, CD8+ and CD2+ splenocytes was lower in transplanted intact mice than that in controls. The CD8+ and CD2+ subsets in the blood of 2 months transplanted mice were higher than those in controls, whereas in PBL, in 10 months old and castrated mice, the T lymphocyte subsets remain unchanged. Depo-testosterone (DT) injection strongly reduced weight and tumor growth in all the intact and castrated animals. A significant correlation is observed between the tumor weight and testosterone level in the plasma of the 2 months old DT treated mice. Moreover, DT injection induced a significant increase in the percentage of blood CD8+ cells in all the batches. These data indicate that physiologically, androgens affect the age-related distribution of lymphocyte T subsets and suggest that they slow down tumor growth, besides causing a direct effect, through an immunological process.

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Cutting Edge: IL-10-Producing CD4+ T Cells Mediate Tumor Rejection

Cited by 71 publications

References 32 publications

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming

Influence of age, castration, and testosterone on T cell subsets in healthy and leukemia grafted mice

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