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

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.

BRCA Mutations, Homologous DNA Repair Deficiency, Tumor Mutational Burden, and Response to Immune Checkpoint Inhibition in Recurrent Ovarian Cancer

“…11 Responses to ICI in OC have been modest, [12][13][14] and it is unclear whether response to ICI varies according to BRCA1/2 mutation status, other markers of HRD, or TMB. Emerging data suggest that the combination of ICI and poly (ADP-ribose) polymerase (PARP) inhibitors may act in an additive or synergistic manner, [15][16][17][18][19] spawning a number of large trials evaluating ICIs in combination with PARP inhibitors. Although these studies highlight that PARP inhibition could engender immunogenicity in OCs, possibly through activation of the cGAS-STING signaling axis, 9 they fail to answer whether BRCA1/2-mutated OCs are inherently more sensitive to ICI because it is difficult to separate the contribution of each therapy within such a setting.…”

Targeting Myeloid-Derived Suppressor Cells in Ovarian Cancer

“…Increased numbers of circulating MDSCs have been detected in patients with various types of cancers [11,14,15]. Like in other cancer patients, as shown (Table 1), MDSCs were significantly increased in the peripheral blood mononuclear cells (PBMC), tumor or ascites in ovarian cancer patients [17,[22][23][24][25][26][27][28][29][30][31][32][33]. Obermajer et al and Cui et al are the first to demonstrate an increased MDSC in the ascites [33] and ovarian tumors [32] of patients with ovarian cancer, respectively.…”

“…Interestingly, two recent reports have suggested an association between decreased MDSCs and favorable treatment outcomes in ovarian cancer patients. Lee et al showed that germline BRCA1 and 2 mutation-associated ovarian cancer, which is believed to have higher response rates to platinum-based chemotherapy than BRCA wild-type [34], has fewer circulating MDSCs and higher CD8 + T cells in PBMC compared with BRCA wildtype ovarian cancer [24]. Second, Li et al demonstrated that metformin treatment in diabetic patients with ovarian cancer was associated with reduced circulating MDSCs, a concomitant increase in the circulating CD8 + T cells, and longer survival [29].…”

Chlamydia trachomatis enhances HPV persistence through immune modulation

“…Regulatory T cells (Tregs) often appear in persistent HPV infection and are positively correlated with the lesion size [39] . The increased level of Tregs in this study was consistent with previous results.…”