The Ratios of CD8+ T Cells to CD4+CD25+ FOXP3+ and FOXP3- T Cells Correlate with Poor Clinical Outcome in Human Serous Ovarian Cancer

Preston, Claudia C.; Maurer, Mathew S.; Oberg, Ann L.; Visscher, Daniel W.; Kalli, Kimberly R.; Hartmann, Lynn C.; Goode, Ellen L.; Knutson, Keith L.

doi:10.1371/journal.pone.0080063

Cited by 183 publications

(173 citation statements)

References 45 publications

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“…Toward this end, we evaluated the phenotype and prognostic significance of CD25 þ TIL subsets in high-grade serous carcinoma (HGSC), the most common and lethal form of ovarian cancer. In accord with prior reports (8,(14)(15)(16) …”

Section: Introductionsupporting

confidence: 91%

“…Furthermore, CD4 is also expressed by macrophages in humans, thus complicating the histopathologic scoring (6). Owing to this complexity, CD4 as a standalone marker has shown no association with patient survival in ovarian cancer (7,8). CD4 þ TIL have been divided into several distinct functional subsets based on cytokine secretion patterns and phenotypic markers (5).…”

Section: Introductionmentioning

confidence: 99%

“…These cells can inhibit tumor immunity by a variety of mechanisms, including the production of immunosuppressive cytokines, depletion of extracellular ATP, and inhibitory cell contacts (13). Accordingly, Tregs have been associated with poor prognosis in ovarian cancer (8,(14)(15)(16) and many other cancer types (1,17). Thus, CD4…”

Section: Introductionmentioning

confidence: 99%

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CD25 Identifies a Subset of CD4+FoxP3− TIL That Are Exhausted Yet Prognostically Favorable in Human Ovarian Cancer

deLeeuw

Kroeger

Kost

et al. 2015

Cancer Immunology Research

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CD25, the alpha subunit of the IL2 receptor, is a canonical marker of regulatory T cells (Treg) and hence has been implicated in immune suppression in cancer. However, CD25 is also required for optimal expansion and activity of effector T cells in peripheral tissues. Thus, we hypothesized that CD25, in addition to demarcating Tregs, might identify effector T cells in cancer. To investigate this possibility, we used multiparameter flow cytometry and IHC to analyze tumor-infiltrating lymphocytes (TIL) in primary high-grade serous carcinomas, the most common and fatal subtype of ovarian cancer. CD25 was expressed primarily by CD4 þ TIL, with negligible expression by CD8 þ TIL.In addition to conventional CD25

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Section: Introductionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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CD25 Identifies a Subset of CD4+FoxP3− TIL That Are Exhausted Yet Prognostically Favorable in Human Ovarian Cancer

deLeeuw

Kroeger

Kost

et al. 2015

Cancer Immunology Research

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“…This increase coincided with a significant increase in the CD8:Treg ratio (Fig. 4J), which has been associated with the sensitivity of a tumor to a given therapy and also with improved overall survival in patients with breast cancer and other cancer subtypes (3,(31)(32)(33). Collectively, these data indicate that directing the CD8 T-cell response using anti-DEC-205/HER2 vaccination enhances the efficacy of combination therapy, reverses Th2 cytokine production by CD4 T cells, and enhances effector CD8 T-cell infiltration into the tumor.…”

Section: Resultsmentioning

confidence: 69%

Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice

Linch

Kasiewicz

McNamara

et al. 2016

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

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Immunotherapy is gathering momentum as a primary therapy for cancer patients. However, monotherapies have limited efficacy in improving outcomes and benefit only a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to improve survival further. Here, we demonstrate that dual aOX40 (anti-CD134)/aCTLA-4 (anti-cytotoxic T-lymphocyte-associated protein 4) immunotherapy generated a potent antigen-specific CD8 T-cell response, enhancing expansion, effector function, and memory T-cell persistence. Importantly, OX40 and CTLA-4 expression on CD8 T cells was critical for promoting their maximal expansion following combination therapy. Animals treated with combination therapy and vaccination using anti-DEC-205 (dendritic and epithelial cells, 205 kDa)-HER2 (human epidermal growth factor receptor 2) had significantly improved survival in a mammary carcinoma model. Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment. Furthermore, this therapy was associated with extensive tumor destruction and T-cell infiltration into the tumor. Notably, in a spontaneous model of prostate adenocarcinoma, vaccination with combination therapy reversed anergy and enhanced the expansion and function of CD8 T cells recognizing a tumor-associated antigen. Collectively, these data demonstrate that the addition of a vaccine with combined aOX40/aCTLA-4 immunotherapy augmented antitumor CD8 T-cell function while limiting Th2 polarization in CD4 cells and improved overall survival.

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“…To further characterize three subtypes of T lymphocytes that are likely to play different roles in the tumor microenvironment, 17,28,29 particularly in malignant effusions, we sorted out T cells in pleural effusion or ascites of three patients using flow cytometry ( Fig. 4A) and examined TCR sequences in each of CD4 C , CD8 C , and CD4 C CD25 C populations ( Fig.…”

Section: The Tcr Analysis Of T Cell Subtype Populations In Malignant mentioning

confidence: 99%

Characterization of T cell repertoire of blood, tumor, and ascites in ovarian cancer patients using next generation sequencing

et al. 2015

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Tumor-infiltrating lymphocytes (TILs) play an important role in regulating the host immune response and are one of key factors in defining tumor microenvironment. Some studies have indicated that T cell infiltration in malignant ascites is associated with clinical outcome, but few studies have performed detailed characterization of T cell diversity or clonality in malignant effusions. We have applied a next generation sequencing method to characterize T cell repertoire of a set of primary cancers, ascites, and blood from 12 ovarian cancer patients and also analyzed the T cell subtype populations in malignant fluids from 3 ovarian cancer patients. We observed enrichment of certain T cells in tumors and ascites, but most of the enriched T cell receptor (TCR) sequences in tumors and ascites were not common. Moreover, we analyzed TCR sequences of T cell subtypes (CD4 C , CD8 C , and regulatory T cells) isolated from malignant effusions and also found clonal expansion of certain T cell populations, but the TCR sequences were almost mutually exclusive among the three subgroups. Although functional studies of clonally expanded T cell populations are definitely required, our approach offers a detailed characterization of T cell immune microenvironment in tumors and ascites that might differently affect antitumor immune response.

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The Ratios of CD8+ T Cells to CD4+CD25+ FOXP3+ and FOXP3- T Cells Correlate with Poor Clinical Outcome in Human Serous Ovarian Cancer

Cited by 183 publications

References 45 publications

CD25 Identifies a Subset of CD4+FoxP3− TIL That Are Exhausted Yet Prognostically Favorable in Human Ovarian Cancer

CD25 Identifies a Subset of CD4+FoxP3− TIL That Are Exhausted Yet Prognostically Favorable in Human Ovarian Cancer

Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice

Characterization of T cell repertoire of blood, tumor, and ascites in ovarian cancer patients using next generation sequencing

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