Patients with BRCA mutated ovarian cancer may have fewer circulating MDSC and more peripheral CD8+ T cells compared with women with BRCA wild‑type disease during the early disease course

Lee,Jung‑Min; Botesteanu,Dana‑Adriana; Tomita,Yusuke; Yuno,Akira; Lee,Min‑Jung; Kohn,Elise  C.; Annunziata,Christina  M.; Matulonis,Ursula; MacDonald,Lauren  A.; Nair,Jayakumar  R.; Macneil,Kimberley  M.; Trepel,Jane  B.

doi:10.3892/ol.2019.10731

Patients with BRCA mutated ovarian cancer may have fewer circulating MDSC and more peripheral CD8+ T cells compared with women with BRCA wild‑type disease during the early disease course

Authors:
- Jung‑Min Lee
- Dana‑Adriana Botesteanu
- Yusuke Tomita
- Akira Yuno
- Min‑Jung Lee
- Elise C. Kohn
- Christina M. Annunziata
- Ursula Matulonis
- Lauren A. MacDonald
- Jayakumar R. Nair
- Kimberley M. Macneil
- Jane B. Trepel
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Affiliations: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA, Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
Published online on: August 7, 2019 https://doi.org/10.3892/ol.2019.10731
Pages: 3914-3924

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Abstract

Immunosuppressive myeloid‑derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are associated with immunologic tolerance and poor prognosis in ovarian cancer (OvCa). We hypothesized that women with germline BRCA1 and BRCA2 mutation‑associated (gBRCAm) OvCa would have fewer circulating immunosuppressive immune cells compared to those with BRCA wild‑type (BRCAwt) disease during their early disease course (<5 years post‑diagnosis) where gBRCAm is a favorable prognostic factor. We collected and viably froze peripheral blood mononuclear cells (PBMCs) from patients with recurrent OvCa olaparib clinical trials (NCT01445418/NCT01237067). Immune subset analyses were performed using flow cytometry for Tregs, exhausted CD8+ T cells, monocytes and MDSCs. Functional marker expression, including cytotoxic T lymphocyte‑associated protein 4 (CTLA‑4), T cell immunoglobulin and mucin domain 3 (TIM‑3) and programmed cell death protein 1 (PD‑1) was evaluated. Data were analyzed using FlowJo. Pretreatment PBMCs were collected from 41 patients (16 gBRCAm/25 BRCAwt). The percentage of MDSCs among viable CD45+ PBMC was lower in gBRCAm OvCa compared with BRCAwt OvCa (median 0.565 vs. 0.93%, P=0.0086) but this difference was not seen in those women >5 years post‑diagnosis. CD8+ T cells among viable CD45+ PBMCs and CTLA‑4+/CD8+ T cells were higher in gBRCAm carriers than patients with BRCAwt, in particular for those <5 years post‑diagnosis (median 20.4 vs. 9.78%, P=0.031 and median MFI 0.19 vs. 0.22, P=0.0074, respectively). TIM‑3 expression on Tregs was associated with poor progression‑free survival, independent of gBRCAm status (P<0.001). Our pilot data suggested that patients with gBRCAm OvCa may have fewer circulating MDSCs but higher CD8+ T cells in PBMCs during their early disease course. This may contribute to the observed survival benefit for these women in their first post‑diagnosis decade.

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