Tumor-associated macrophage expression of PD-L1 in implants of high grade serous ovarian carcinoma: A comparison of matched primary and metastatic tumors

Gottlieb, Chelsea E.; Mills, Anne M.; Cross, Janet V.; Ring, Kari L.

doi:10.1016/j.ygyno.2016.12.021

Cited by 62 publications

(64 citation statements)

References 18 publications

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“…Higher PD-L1 expression predicts inferior survival in several cancer forms [34], supporting the theory of tumor cells upregulating PD-L1 in order to suppress T cells, thereby promoting tumor growth. In contrast, previous studies in HGSC, in addition to our cohort and in silico validation presented herein, have shown a survival benefit of high PD-L1 expression in macrophages [19,28,29]. Interestingly, high PD-1 expression was associated with an even stronger survival benefit when the analysis was restricted to cases with high CD3 expression.…”

Section: Discussioncontrasting

confidence: 96%

“…In this study, we found that PD-L1 was expressed mainly by macrophages, which has previously been reported [19,28,29] and not by tumor cells as some previous studies suggest [17,18,20,30]. Remarkably, macrophage staining, which was necessary for the correct mapping of PD-L1 expression in Values in italics are statistically significant (P < 0.05) a Intra-epithelial CD3 expression, PD-1 expression in intra-epithelial lymphocytes, and PD-L1 expression in intra-epithelial macrophages Multivariable analysis of each immune marker including well-known prognostic factors above.…”

Section: Discussionsupporting

confidence: 81%

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PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma

et al. 2020

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The response rate to checkpoint inhibitors for women with high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is modest, and development of predictive biomarkers is needed. The main focus has been on tumor cell PD-L1 expression, but its assessment alone is insufficient for patient selection in most malignancies. We mapped the presence of macrophages (CD68 and CD163) and lymphocytes (CD3) located within the tumor epithelium, the cell type-specific expression of PD-L1 and PD-1, and their impact on 5-year overall survival (OS) in a consecutive cohort of 130 women diagnosed with advanced HGSC between 2011 and 2015. PD-L1 was expressed mainly by macrophages (not by tumor cells) and PD-1 by lymphocytes. Women with higher CD3, PD-L1, and PD-1 expression had improved OS (P = 0.03, P = 0.007, and P = 0.02, respectively). In the external data set (203 women), high expression of CD274 (encoding PD-L1) was associated with improved OS (P = 0.03), in accordance with our results. Furthermore, higher CD163 expression was associated with better outcome in women with no residual tumor after primary surgery (P = 0.02). Thus, women with greater lymphocyte tumor infiltration had better outcome and PD-L1/PD-1 expression, regardless of PD-1/PD-L1 being markers for immune suppressive pathways, conferred a survival benefit in our cohort. Our results highlight that tumor immunity may be harnessed in subsets of HGSC.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionsupporting

confidence: 81%

PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma

et al. 2020

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“…TAMs demonstrated a primary expression of PD-L1 in ovarian carcinoma, and patients with high PD-L1 expression levels have significantly worse survival than cases of low PD-L1 expression (35). We further accessed the expression of PD-L1 on AZD5153-treated M2-like macrophages.…”

Section: Azd5153 Sensitizes Ovarian Cancer To αPd-l1mentioning

confidence: 99%

BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

Yang

et al. 2020

Front. Immunol.

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High-grade serous ovarian cancer (HGSOC), with its high recurrence rates, urges for reasonable therapeutic strategies that can prolong overall survival. A tumor microenvironment (TME) discloses prognostic and prospective information on cancer, such as the expression level of PD-1 or PD-L1. However, in HGSOC, the impact of the therapies aiming at these targets remains unsatisfying. Tumor-associated macrophages (TAMs) in HGSOC make up a large part of the TMEs and transform between diverse phenotypes under different treatments. AZD5153 inhibiting BRD4, as a potential therapeutic strategy for HGSOC, was demonstrated to confer controversial plasticity on TAMs, which shows the need to uncover its impact on TAMs in HGSOC. Therefore, we established models for TAMs and TAMs co-culturing with T lymphocytes in vitro. Via RT-PCR and flow cytometry, we find that AZD5153 resets TAMs from M2-type macrophages to M1-like macrophages, consequently promoting pro-inflammatory cytokine secretion and thus activating CD8 + cytotoxic T lymphocytes (CTLs) in vitro. This modification occurs on MAF transcripts in TAMs and modified by BRD4, which is the target of AZD5153. Importantly, the 3-D microfluid model demonstrates that AZD5153 sensitizes ovarian cancer to anti-PD-L1 therapy. Our results clarify that besides eliminating tumor cells directly, AZD5153 works as a regulator of the TAM phenotype, providing a novel strategy combining AZD5153 and PD-1/PD-L1 antibody that could benefit HGSOC patients.

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“…Interestingly, neoadjuvant chemotherapy has an influence on TME in high‐grade OC and may contribute to higher PD‐L1 expression in TAMs. However, there are incompatible data and this hypothesis should be confirmed . Therefore, it is necessary to conduct studies to confirm the underlying mechanism in different grades and histological types of OC .…”

Section: Combined Therapiesmentioning

confidence: 99%

“…Some authors show that primary tumors and metastatic implants have distinct mutational profiles [38]. Others have observed PD-L1 expression in HGSOC TAM in both primary and metastatic sites [39]. In a study conducted by Ojalvo et al [40], expression of PD-L1 by both tumor cells and TAM in recurrent tumors led to the development of an active immune response and imparted better survival in recurrent OC in relation to primary cancer, whereas only TAM expressed PD-L1.…”

Section: Evading Anti-tumor Responsementioning

confidence: 99%

Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment

Pawłowska

Suszczyk

Okła

et al. 2019

Clinical and Experimental Immunology

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Summary Immunotherapies based on anti‐programmed death 1/programmed death ligand 1 (PD‐1/PD‐L1) pathway inhibitors may turn out effective in ovarian cancer (OC) treatment. They can be used in combination with standard therapy and are especially promising in recurrent and platinum‐resistant OC. There is growing evidence that the mechanism of the PD‐1/PD‐L1 pathway can be specific for a particular histological cancer type. Interestingly, the data have shown that the PD‐1/PD‐L1 pathway blockade may be effective, especially in the endometrioid type of OC. It is important to identify the cause of anti‐tumor immune response suppression and exclude its other mechanisms in OC patients. It is also necessary to conduct subsequent studies to confirm in which OC cases the treatment is effective and how to select patients and combine drugs to improve patient survival.

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Tumor-associated macrophage expression of PD-L1 in implants of high grade serous ovarian carcinoma: A comparison of matched primary and metastatic tumors

Cited by 62 publications

References 18 publications

PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma

PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma

BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment

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