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      Natural Compounds with Potential to Modulate Cancer Therapies and Self-Reactive Immune Cells

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          Abstract

          Cancer-related deaths are approaching 10 million each year. Survival statistics for some cancers, such as ovarian cancer, have remained unchanged for decades, with women diagnosed at stage III or IV having over 80% chance of a lethal cancer recurrence after standard first-line treatment (reductive surgery and chemotherapy). New treatments and adjunct therapies are needed. In ovarian cancer, as in other cancers, the immune response, particularly cytotoxic (CD8 +) T cells are correlated with a decreased risk of recurrence. As well as completely new antigen targets resulting from DNA mutations (neo-antigens), these T cells recognize cancer-associated overexpressed, re-expressed or modified self-proteins. However, there is concern that activation of self-reactive responses may also promote off-target pathology. This review considers the complex interplay between cancer-reactive and self-reactive immune cells and discusses the potential uses for various leading immunomodulatory compounds, derived from plant-based sources, as a cancer therapy option or to modulate potential autoimmune pathology. Along with reviewing well-studied compounds such as curcumin (from turmeric), epigallocatechin gallate (EGCG, from green tea) and resveratrol (from grapes and certain berries), it is proposed that compounds from novel sources, for example, native Australian plants, will provide a useful source for the fine modulation of cancer immunity in patients.

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          Most cited references156

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          Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis.

          The presence of T cells within the epithelial component of tumors, as histologic evidence of anti-tumor immunity, has been associated with a survival advantage in multiple studies across diverse patient cohorts. We performed a meta-analysis of studies evaluating the prognostic value of tumor-infiltrating lymphocytes (TIL) on survival among women with ovarian cancer and to investigate factors associated with variations in this effect, including patient characteristics, surgical outcomes, tumor histology, and study protocols. Published studies that evaluated the association between TIL and patient survival were identified. Descriptive statistics, outcome data, and study quality were extracted from studies that met inclusion criteria. Hazard ratios and 95% confidence intervals were pooled across studies using the random-effects model. Publication bias was investigated using a funnel plot and heterogeneity was assessed with subgroup analysis and I(2) statistics. Ten suitable studies comprising 1815 patients with ovarian cancer were analyzed. Our results demonstrate that a lack of intraepithelial TILs is significantly associated with a worse survival among patients (pooled HR: 2.24, 95% CI; 1.71-2.91). Variations in the prognostic value of TIL status based on debulking status, scoring method, and geographic regions were identified. Intraepithelial TILs are a robust predictor of outcome in ovarian cancer and define a specific class of patients, whose distinct tumor biology should be taken into account in devising appropriate therapeutic strategies. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis

            To evaluate rates of serious organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems for anti-programmed cell death 1 (PD-1) drugs overall and compared with control treatments.
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              PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness

              Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of single-stranded DNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions, which in turn activated the DNA sensing cGAS-STING pathway and stimulated production of type I interferons to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                13 March 2020
                March 2020
                : 12
                : 3
                : 673
                Affiliations
                School of Health and Biomedical Sciences, RMIT, Bundoora 3083, Australia; s3740510@ 123456student.rmit.edu.au (R.M.); kirsty.wilson2@ 123456rmit.edu.au (K.W.); anthony.jaworowski@ 123456rmit.edu.au (A.J.)
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-7679-9611
                https://orcid.org/0000-0001-6889-3667
                Article
                cancers-12-00673
                10.3390/cancers12030673
                7139800
                32183059
                45b66d45-4c87-4536-a5ef-9f6bd1c11331
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 February 2020
                : 11 March 2020
                Categories
                Review

                self-reactive,natural compounds,immune response,ovarian cancer,native australian plants,immunotherapy

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