Effector Function of Human Tumor-Specific CD8 T Cells in Melanoma Lesions: A State of Local Functional Tolerance

Zippelius, Alfred; Batard, Pascal; Rubio-Godoy, Verena; Bioley, Gilles; Líénard, Danielle; Lejeune, Ferdy J.; Rimoldi, Donata; Guillaume, Philippe; Meidenbauer, Norbert; Mackensen, Andréas; Rufer, Nathalie; Lübenow, Norbert; Speiser, Daniel E.; Cerottini, Jean‐Charles; Romero, Pedro; Pittet, Mikaël J.

doi:10.1158/0008-5472.can-03-3066

Cited by 342 publications

(325 citation statements)

References 42 publications

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“…However, in many tumor entities and tumor models, CD8 + T cells are exhausted and impaired to control tumor spread, which likely contributes to the often-observed limited efficacy of immunotherapy (28). Previously we demonstrated that tumor-specific CD4 + T cells apart from being helper cells can substitute for the function of CD8 + T cells and efficiently control tumor growth (13).…”

Section: Discussionmentioning

confidence: 99%

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Akhmetzyanova

Zelinskyy

Littwitz-Salomon

et al. 2016

The Journal of Immunology

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Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus–induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4+ T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8+ T cell–deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4+ T cells. Interestingly, a subset of CD4+Foxp3+ regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-α or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4+ T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3+CD4+ T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Akhmetzyanova

Zelinskyy

Littwitz-Salomon

et al. 2016

The Journal of Immunology

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“…Both MAA selected for the present in vitro study (MelanA/MART-1 and gp100) are the targets of CTL that can be identified in blood and tumor infiltrates of melanoma patients [47]. Nevertheless, the in vivo anti-tumoral efficiency of these T cells has not been demonstrated [48]. Immunotherapeutical trials using these two antigens as short MHC I peptides have been used for the treatment of metastatic melanoma in order to induce or amplify tumor-specific T cells.…”

Section: Discussionmentioning

confidence: 99%

Long‐lasting cross‐presentation of tumor antigen in human DC

et al. 2009

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DC cross-present exogenous antigens on MHC class I molecules, a process required for the onset of anti-tumor immune responses. In order to study the cross-presentation of tumor antigens by human DC, we compared the pathways of cross-presentation of long peptides requiring internalization and intracellular processing with the direct presentation of short peptides, which does not require intracellular processing. We found that, after brief incubations with DC, short peptides were presented to CD8 1 T cells with higher efficiencies than long peptides. After longer times of chase in the absence of peptide, however, the efficiency of presentation of the two types of peptides was reversed. After 2-3 days, DC pulsed with long peptides still activated T cells efficiently, while DC pulsed with short peptides failed to do so. Long-lasting presentation of the long peptides was, at least in part, due to a stored persistent pool of antigen, which was still available for loading on MHC class I molecules after several days of chase. These results show that the use of long synthetic peptides allows the efficient, long-lasting, presentation of tumor antigens, suggesting that long peptides represent an interesting approach for active anti-tumor vaccination.Key words: Cross-presentation . CTL . DC . Long peptides . Melanoma-associated antigen Supporting Information available online IntroductionAdaptative immune responses, especially through CD8 1 T cells, can induce the rejection of solid tumors [1][2][3]. Endogenously expressed tumor-associated antigens (TAA) expressed in tumor cells are recognized by CTL through cognate interactions of the TCR with class I MHC molecules associated with 8-10 amino acid long antigenic peptides. These tumor cell/T-cell interactions, however, are not sufficient to activate naïve T lymphocytes and to induce a memory response. Indeed, professional APC are required for the induction of effector and memory tumor-specific immune responses [4,5]. As most often APC do not endogenously express TAA, uptake and presentation of antigen via an exogenous pathway is required. This so-called ''cross-presentation'' pathway is mainly performed by DC [6,7]. Following the initial observations of cross-priming of T cells by bone-marrowderived cells [8,9], numerous studies investigated the role of cross-priming in the induction of anti-tumor immune responses [10][11][12][13][14] and the strategies to manipulate cross-priming to induce and amplify tumor-specific immune responses [15][16][17][18][19]. Because 380they display a unique capacity to efficiently cross-present exogenous antigens and to prime naïve CD8 1 T cells, DC are good candidates for cancer immunotherapy. The DC-based cancer vaccines that have been tested successfully in mouse models include DC loaded with different forms of tumor antigens, including short peptides, tumor extracts, tumor-derived membrane vesicles and tumor-derived RNA [20][21][22][23]. Nevertheless, these cell-based vaccines present some disadvantages, mainly related to their cost and the...

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“…[29][30][31] Although CTL induction by prophylactic vaccinations has been reported to be important for tumor elimination, 32,33 CTLs generated by established tumors are ineffective. 34 In this study, we found that the growth of tumors expressing tumor Ag (Her2/CT26 and TC-1) was more inhibited in Myd88 À/À mice than in WT mice. Based on the expression of xenogenic human Her-2/neu on CT26 murine colon carcinoma, Ag-specific immunity seemed to work differently in Myd88 À/À mice and WT mice.…”

Section: Discussionmentioning

confidence: 63%

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

Hong

Chang

Lee

et al. 2012

Intl Journal of Cancer

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Myd88 is an important adaptor molecule for the activation of NADPH oxidase and arginase-1, which are responsible for the suppressive function of myeloid-derived suppressor cells (MDSCs). When wild-type and Myd88 2/2 mice were subcutaneously injected with CT26 colon cancer cells expressing human Her-2/neu, tumor growth was retarded in Myd88 2/2 mice than in wild-type mice. Although the generation of CD11b 1 Gr-1 1 MDSCs was less in Myd88 2/2 mice than in wild-type mice, Myd88 2/2 mice having tumor masses still had significant quantities of MDSCs, suggesting that MDSC generation might be independent of Myd88 signaling. However, MDSCs obtained from tumor-bearing Myd88 2/2 mice failed to suppress antigenspecific proliferation of CD8 1 T cells and CD4 1 T cells, whereas MDSCs from wild-type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88 2/2 mice compared with wild-type mice after tumor challenge. Furthermore, CD4 1 T cells residing in tumor-draining lymph nodes of Myd88 2/2 mice secreted more TNF-a than those of wild-type mice. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors. Overall, these data suggest that signaling through the Myd88 adaptor molecule is critical for the direct suppressive function of MDSCs and approaches to block Myd88-mediated signaling in MDSCs might be effective to inhibit the immunosuppressive function of MDSCs.

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Effector Function of Human Tumor-Specific CD8 T Cells in Melanoma Lesions: A State of Local Functional Tolerance

Cited by 342 publications

References 42 publications

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Long‐lasting cross‐presentation of tumor antigen in human DC

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

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