TY - JOUR
T1 - Expression of B7–H4 and IDO1 is associated with drug resistance and poor prognosis in high-grade serous ovarian carcinomas
AU - Niu, Na
AU - Shen, Weiwei
AU - Zhong, Yanping
AU - Bast, Robert C.
AU - Jazaeri, Amir
AU - Sood, Anil K.
AU - Liu, Jinsong
N1 - Funding Information:
Funding/support: This work is supported by The University of Texas MD Anderson Cancer Center SPORE grant (P50CA217685), MD Anderson Moonshot in Ovarian Cancer, the American Cancer Society , and the Frank McGraw Memorial Chair in Cancer Research . Multiplex IHC was performed in the Flow Cytometry & Cellular Imaging Facility — north campus, which is supported in part by the National Institutes of Health through MD Anderson's Cancer Center Support Grant CA016672. This paper was edited by Sarah Bronson, ELS, at MD Anderson Cancer Center.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/7
Y1 - 2021/7
N2 - High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7–H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7–H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7–H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7–H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7–H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.
AB - High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7–H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7–H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7–H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7–H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7–H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.
KW - B7–H4
KW - Drug resistance
KW - IDO1
KW - Immunotherapy
KW - Ovarian carcinoma
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U2 - 10.1016/j.humpath.2021.04.003
DO - 10.1016/j.humpath.2021.04.003
M3 - Article
C2 - 33887301
AN - SCOPUS:85106364618
SN - 0046-8177
VL - 113
SP - 20
EP - 27
JO - Human Pathology
JF - Human Pathology
ER -