Immunotherapy for Ovarian Cancer

Drerup, Justin; Liu, Yang; Padrón, Álvaro; Murthy, Kruthi; Hurez, Vincent; Zhang, Bin; Curiel, Tyler J.

doi:10.1007/s11864-014-0317-1

Cited by 27 publications

(22 citation statements)

References 103 publications

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“…In consideration of the great resistance that can be caused by first-line chemoreagents clinically employed in clinics, immunotherapy that could circumvent the resistance in the chemotherapy of cancer deserves to be explored. 9,10 In our previous work, to make clear the differential cytokines between patients with EOC versus healthy controls, the differential cytokines were screened using antibody microchip technique revealing that IL-36α was significantly downregulated in sera from patients with EOC compared with healthy control (unpublished). Given the paucity of data regarding IL-36α in cancer, IL-36α was picked up as a cytokine of interest in the following functional analysis.…”

Section: Discussionmentioning

confidence: 99%

IL-36α suppresses proliferation of ovarian cancer cells

2017

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Interleukin-36α (IL-36α), also formerly known as IL-1F6, is pertaining to IL-1 family members that has been shown to play an important pro-inflammatory role in chronic immune disorders. However, the role IL-36α in the setting of cancer remains unknown. Here, in our study, to investigate the clinical relevance of IL-36α in ovarian cancer, clinicopathological significance as well as expression level of IL-36α were analyzed in epithelial ovarian cancer clinical tissues and paired normal control. To explore the biological role of IL-36α in vitro in epithelial ovarian cancer cells, both overexpression and knockdown of IL-36α were performed. Based on the successful re-expression and silencing of IL-36α, proliferation, migration, and invasion were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound-healing, and Transwell assays, respectively. To further confirm the effect over proliferation in vivo, nude mice xenografted with epithelial ovarian cancer cells whose endogenous IL-36α was stably upregulated or downregulated were employed. It was found that IL-36α was shown to be markedly downregulated in epithelial ovarian cancer tissues relative to paired normal control and that reduced IL-36α expression was significantly associated with poor overall prognosis. In addition, IL-36α was observed to be able to suppress the growth of epithelial ovarian cancer cells both in vivo and in vitro. Taken together, IL-36α was displayed to be able to suppress the growth of epithelial ovarian cancer cells in our setting, which is suggestive of its druggable potential in curing the epithelial ovarian cancer and that upregulation of IL-36α was found to be capable of inhibiting the growth of epithelial ovarian cancer cells.

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Section: Discussionmentioning

confidence: 99%

IL-36α suppresses proliferation of ovarian cancer cells

2017

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“…These analyses are in the context of standard treatment regimes; neoantigens may have a greater impact for patients treated with immunotherapies. However, as immunotherapy trials in HGSC have focused on heavily pre-treated patients with recurrent disease, the substantially increased total neoantigen burden at recurrence is evidently not sufficient on its own for immunotherapy to be effective for many patients [31][32][33][34]. Other factors, perhaps unique ascitic or systemic immunosuppressive mechanisms, may also need to be overcome.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer

O’Donnell

Christie

Buros

et al. 2016

Preprint

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Background: Patients with highly mutated tumors, such as melanoma or smoking-related lung cancer, have higher rates of response to immune checkpoint blockade therapy, perhaps due to increased neoantigen expression. Many chemotherapies including platinum compounds are known to be mutagenic, but the impact of standard treatment protocols on mutational burden and resulting neoantigen expression in most human cancers is unknown. Methods: We sought to quantify the effect of chemotherapy treatment on computationally predicted neoantigen expression for high grade serous ovarian carcinoma patients enrolled in the Australian Ovarian Cancer Study. In this series, 35 of 114 samples were collected after exposure to chemotherapy; 14 are matched with an untreated sample from the same patient. Our approach integrates whole genome and RNA sequencing of bulk tumor samples with class I MHC binding prediction and mutational signatures extracted from studies of chemotherapy-exposed Caenorhabditis elegans and Gallus gallus cells. We additionally investigated the relationship between neoantigens, tumor infiltrating immune cells estimated from RNA-seq with CIBERSORT, and patient survival. Results: Greater neoantigen burden and CD8+ T cell infiltration in primary, pre-treatment samples were independently associated with improved survival. Relapse samples collected after chemotherapy harbored a median of 78% more expressed neoantigens than untreated primary samples, a figure that combines the effects of chemotherapy and other processes operative during relapse. The contribution from chemotherapy-associated signatures was small, accounting for a mean of 5% (range 0-16) of the expressed neoantigen burden in relapse samples. In both treated and untreated samples, most neoantigens were attributed to COSMIC Signature (3), associated with BRCA disruption, Signature (1), associated with a slow mutagenic process active in healthy tissue, and Signature (8), of unknown etiology. Conclusion: Relapsed ovarian cancers harbor more predicted neoantigens than primary tumors, but the increase is due to pre-existing mutational processes, not mutagenesis from chemotherapy.

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“…Given T cell toxicities of typical rapamycin, potentially improved T cell functions with LD rapamycin and reports that LD improves antigen-specific T cell functions (14,25), we asked if LD rapamycin would improve treatment for EL4 in combination with immunotherapies showing promise in epithelial carcinomas (33,34). We thus also assessed EL4 for other candidate tumor immunotherapy targets by flow cytometry and found that EL4 cells expressed low B7-H1 (PD-L1) and high PD-1, but negligible CD25 and CTLA-4 (Suppl.…”

Section: Resultsmentioning

confidence: 99%

Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment

et al. 2017

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mTOR drives tumor growth but also supports T cell function, rendering the applications of mTOR inhibitors complex especially in T cell malignancies. Here we studied the effects of the mTOR inhibitor rapamycin in mouse EL4 T cell lymphoma. Typical pharmacologic rapamycin (1–8 mg/kg) significantly reduced tumor burden via direct suppression of tumor cell proliferation and improved survival in EL4 challenge independent of anti-tumor immunity. Denileukin diftitox (DD)-mediated depletion of regulatory T cells significantly slowed EL4 growth in vivo in a T cell-dependent fashion. However, typical rapamycin inhibited T cell activation and tumor infiltration in vivo and failed to boost DD treatment effects. Low dose rapamycin (LD, 75 μg/kg) increased potentially beneficial CD44hiCD62L+ CD8+ central memory T cells in EL4 challenge, but without clinical benefit. LD rapamycin significantly enhanced DD treatment efficacy, but DD plus LD rapamycin treatment effects were independent of anti-tumor immunity. Instead, rapamycin up-regulated EL4 IL-2 receptor in vitro and in vivo, facilitating direct DD tumor cell killing. LD rapamycin augmented DD efficacy against B16 melanoma and a human B cell lymphoma, but not against human Jurkat T cell lymphoma or ID8agg ovarian cancer cells. Treatment effects correlated with IL-2R expression, but mechanisms in some tumors were not fully defined. Overall, our data define a distinct, biphasic mechanisms of action of mTOR inhibition at doses that are clinically exploitable, including in T cell lymphomas.

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Immunotherapy for Ovarian Cancer

Cited by 27 publications

References 103 publications

IL-36α suppresses proliferation of ovarian cancer cells

IL-36α suppresses proliferation of ovarian cancer cells

Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer

Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment

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