Systematic Analysis of Immune Infiltrates in High-Grade Serous Ovarian Cancer Reveals CD20, FoxP3 and TIA-1 as Positive Prognostic Factors

Milne, Katy; Köbel, Martin; Kalloger, Steven E.; Barnes, Rebecca; Gao, Dongxia; Gilks, C. Blake; Watson, Peter H.; Nelson, Brad H.

doi:10.1371/journal.pone.0006412

Cited by 387 publications

(383 citation statements)

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confidence: 76%

“…1 In support of this, the accumulation of tumor-infiltrating lymphocytes significantly correlate with increased survival in HGSC patients. 1 Additionally, recent early phase clinical trials have reported clinical activity (including complete responses) in some patients with HGSC in response to PD-1/PD-L1 blockade. Notwithstanding some encouraging clinical responses following monotherapy with ICI, the presence of multiple non-redundant immunosuppressive mechanisms will likely contribute to resistance or lack of activity for many patients.…”

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confidence: 76%

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CD73-adenosine reduces immune responses and survival in ovarian cancer patients

et al. 2016

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confidence: 76%

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CD73-adenosine reduces immune responses and survival in ovarian cancer patients

et al. 2016

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“…These markers were not associated with improved outcomes in our relatively small cohort of highgrade serous carcinomas but other series with greater case numbers have consistently demonstrated immune cell infiltrates to be a favorable prognostic factor. 18,19,22,24,59 TP53 abnormalities (loss of expression, which correlates with nonsense mutations or deletions, or overexpression, which correlates with missense mutations) were essentially ubiquitous in high-grade serous cancers with BRCA1 or BRCA2 abnormalities and also were associated with favorable outcome. Thus BRCA mutations, immune cell infiltrates, and TP53 abnormalities co-vary in high-grade serous carcinomas.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 Tumors from women with high-grade serous cancers frequently show a host immune response, and the presence of cytotoxic T lymphocytes, and T-regulatory cells is consistently associated with favorable prognosis. [18][19][20][21][22][23][24] Germline mutations in BRCA1 and BRCA2 are present in B18% of ovarian cancer patients with high-grade serous carcinoma. [25][26][27] When combined with BRCA deficiencies that result from somatic mutations or epigenetic silencing, it appears that up to half of all high-grade serous ovarian cancers (hereditary and sporadic) have BRCA dysfunction.…”

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confidence: 99%

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

et al. 2012

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We characterized BRCA1 and BRCA2 status (mutation/methylation) in a consecutive series of cases of ovarian carcinoma in order to identify differences in clinicopathological features, molecular characteristics, and outcome between the pelvic high-grade serous cancers with (i) germline or somatic mutations in BRCA1 or BRCA2, (ii) methylation of BRCA1, and (iii) normal BRCA1 or BRCA2. In all, 131 women were identified prospectively, who were undergoing surgical staging and agreed to germline testing for BRCA1 and BRCA2 mutations. Histopathology, germline and somatic BRCA1 or BRCA2 mutations, BRCA1 methylation, and BRCA1 and BRCA2 mRNA expression levels distinguished four subgroups. In all, 103 cases were high-grade serous carcinoma and of these 31 (30%) had germline or somatic BRCA1 or BRCA2 mutations (20% BRCA1 and 10% BRCA2) (group 1), 21 (20%) had methylation of BRCA1 (group 2), and in 51 (50%) there was no BRCA loss (group 3). Group 4 consisted of 28 cases of non-high-grade serous, none of which had BRCA loss. BRCA1 and BRCA2 mRNA expression levels correlated with designated group (P ¼ 0.0008). Among high-grade serous carcinomas, there were no differences between groups 1-3 with respect to stage, ascites, CA125 level, platinum sensitivity, cytoreduction rate, neoadjuvant chemotherapy, or survival. Tumors with BRCA1 or BRCA2 mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous without mutations (P ¼ 0.034, 0.027). TP53 expression differed between groups (Po0.0001), with abnormal TP53 expression in 49/50 tumors from groups 1 and 2. Wild-type TP53 expression was associated with worse outcome in high-grade serous (Po0.001). BRCA loss (mutation/methylation) is a common event in the pelvic high-grade serous (50%). TP53 abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous with germline and somatic mutations in BRCA1 or BRCA2, compared with tumors lacking BRCA abnormalities.

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“…Moreover, TIL are often abundant in late-stage tumors yet have obviously failed to prevent tumor progression (15)(16)(17)(18)(19). Together, these features suggest that TIL in ovarian cancer may have experienced prolonged exposure to their cognate antigen and, as a consequence, may be functionally exhausted.…”

Section: Introductionmentioning

confidence: 99%

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

Webb

Milne

Nelson

2015

Cancer Immunology Research

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a E (CD103)b 7 is a TGFb-regulated integrin that mediates retention of lymphocytes in peripheral tissues by binding to E-cadherin expressed on epithelial cells. We recently reported that a E (CD103)b 7 specifically demarcates intraepithelial CD8 þ tumor-infiltrating lymphocytes (CD8 TIL) in ovarian cancer and that CD103 þ TIL have a surface profile consistent with an active effector phenotype (HLA-DR þ , Ki67 þ , and CD127 lo ). These findings led us to hypothesize that, over time, CD103-mediated retention of CD8 TIL within the tumor epithelium might result in chronic stimulation by tumor antigen, which in turn might lead to an exhausted phenotype. To investigate this possibility, we evaluated PD-1 expression in a large cohort of ovarian tumors (N ¼ 489) with known CD103 þ TIL content. PD-1 þ cells were present in 38.5% of high-grade serous carcinomas (HGSC), but were less prevalent in other histologic subtypes. PD-1 þ TIL were strongly associated with increased disease-specific survival in HGSC (HR, 0.4864; P ¼ 0.0007). Multicolor immunohistochemistry and flow cytometry revealed a high degree of PD-1 and CD103 coexpression, specifically within the CD8 TIL compartment. PD-1 þ CD103 þ CD8 TIL were quiescent when assessed directly ex vivo yet were capable of robust cytokine production after pharmacologic stimulation. Moreover, they showed negligible expression of additional exhaustion-associated markers, including TIM-3, CTLA-4, and LAG-3. Thus, as hypothesized, CD103 þ CD8 TIL express PD-1 and appear quiescent in the tumor microenvironment. However, these cells retain functional competence and demonstrate strong prognostic significance. We speculate that, after standard treatment, PD-1 þ CD103 þ CD8 TIL might regain functional antitumor activity, an effect that potentially could be augmented by immune modulation. Cancer Immunol Res; 3(8); 926-35. Ó2015 AACR.

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Systematic Analysis of Immune Infiltrates in High-Grade Serous Ovarian Cancer Reveals CD20, FoxP3 and TIA-1 as Positive Prognostic Factors

Cited by 387 publications

References 126 publications

CD73-adenosine reduces immune responses and survival in ovarian cancer patients

CD73-adenosine reduces immune responses and survival in ovarian cancer patients

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

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