Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen

Cannon, Martin J.; Goyne, Hannah; Stone, Pamela J.B.; MacDonald, Laura J.; James, Lindsey E.; Cobos, Everardo; Chiriva‐Internati, Maurizio

doi:10.1007/s00262-013-1391-0

Cited by 26 publications

(32 citation statements)

References 50 publications

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“…Several mechanisms of tumor-mediated immunesuppression have been identified, including Treg infiltration, expression of B7-H1 and B7-H4 coinhibitory molecules by tumor cells and tumor-associated antigen-presenting cells [26]. Here, we focus on the role of CD8 + Treg in tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment

Chen

Lou

et al. 2016

Oncotarget

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Section: Discussionmentioning

confidence: 99%

TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment

Chen

Lou

et al. 2016

Oncotarget

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“…Inhibitors of the p38 MAP kinase pathway reduce transcription of PD-L1 by DC and may thereby enhance DC-based cancer vaccines [43]. However, these drugs cannot be used in vivo, so other therapy strategies are needed.…”

Section: Discussionmentioning

confidence: 99%

Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells

Ostrand‐Rosenberg

Horn

Álvarez

2015

Cancer Immunol Immunother

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We previously developed cell-based vaccines as therapeutics for metastatic cancers. The vaccines were aimed at activating type I CD4+T cells and consisted of tumor cells transfected with genes encoding syngeneic MHC class II and CD80 costimulatory molecules, and lacking the MHC II-associated invariant chain. The vaccines showed some efficacy in mice with sarcoma, melanoma, and breast cancer and activated MHC class II syngeneic T cells from breast, lung, and melanoma patients. During the course of the vaccine studies, we observed that CD80 not only costimulated naïve T cells, but also bound to PD-L1 and prevented tumor cell-expressed PD-L1 from binding to its receptor PD-1 on activated T cells. A soluble form of CD80 (CD80-Fc) had the same effect and sustained IFNγ production by both human and murine PD-1+ activated T cells in the presence of PD-L1+ human or mouse tumor cells, respectively. In vitro studies with human tumor cells indicated that CD80-Fc was more effective than antibodies to either PD-1 or PD-L1 in sustaining T cell production of IFNγ. Additionally, in vivo studies with a murine tumor demonstrated that CD80-Fc was more effective than antibodies to PD-L1 in extending survival time. Studies with human T cells blocked for CD28 and with T cells from CD28 knockout mice demonstrated that CD80-Fc simultaneously inhibited PD-L1/PD-1-mediated immune suppression and delivered costimulatory signals to activated T cells, thereby amplifying T cell activation. These results suggest that CD80-Fc may be a useful monotherapy that minimizes PD-1 pathway immune suppression while simultaneously activating tumor-reactive T cells.

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“…Epstein-Barr virus-transformed LCL were established from peripheral blood leukocytes (PBL) by infection with the B95.8 strain of Epstein-Barr virus, as described 9 .…”

Section: Methodsmentioning

confidence: 99%

“…In sharp contrast, ovarian tumor expression of IL-17 (produced by infiltrating Th17 T cells) correlates with markedly prolonged overall survival among ovarian cancer patients 6 , leading to the question of whether Th17 cells could be induced or expanded to therapeutic advantage 7,8 . Recent studies have shown that treatment of ovarian tumor antigen-loaded, cytokine-matured dendritic cells (DC) with IL-15 and a p38 MAPK inhibitor (designated DC IL-15/p38inhib ) enhances ERK phosphorylation and biases human CD4 + T cell responses toward a Th1/Th17 phenotype that correlates with strong CD8 + CTL activation 9 .…”

Section: Introductionmentioning

confidence: 99%

Ovarian Tumor Ascites CD14+ Cells Suppress Dendritic Cell–activated CD4+ T-cell Responses Through IL-10 Secretion and Indoleamine 2,3-Dioxygenase

Goyne

Stone²,

Burnett³

et al. 2014

Journal of Immunotherapy

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The observation that Th17 infiltration in ovarian cancer correlates with markedly improved survival has prompted the question of whether ovarian tumor antigen-specific Th17 responses to could be stimulated by tumor vaccination. Dendritic cells treated with IL-15 and an inhibitor of p38 MAPK signaling (DCIL-15/p38inhib) bias T cell responses toward a Th1/Th17 phenotype, raising the prospect of therapeutic vaccination, but significant barriers remain. Tumor vaccines, including DC vaccination, usually stimulate immune responses, but the lack of clinical responses in cancer patients has been disappointing. Possible reasons may include an inability of anti-tumor T cells to migrate into the tumor microenvironment, and an inability of T cells to retain effector function in the face of tumor-associated immune suppression. We found that ovarian tumor antigen-specific CD4+ T cells induced by DCIL-15/p38inhib migrated in response to CXCL12 and CCL22 (both highly expressed in ovarian cancer), and ascites CD14+ myeloid cells. Cocultures showed that ascites CD14+ cells markedly suppressed antigen-specific CD4+ T responses, but suppression could be alleviated by treatment with anti-IL-10 or inhibition of indoleamine 2,3-dioxygenase (IDO). These results suggest that the efficacy of DC vaccination against ovarian cancer may be boosted by agents that inhibit tumor-associated CD14+ myeloid cell suppression or IDO activity.

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Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen

Cited by 26 publications

References 50 publications

TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment

TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment

Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells

Ovarian Tumor Ascites CD14+ Cells Suppress Dendritic Cell–activated CD4+ T-cell Responses Through IL-10 Secretion and Indoleamine 2,3-Dioxygenase

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