The current landscape of predictive and prognostic biomarkers for immune checkpoint blockade in ovarian cancer

Xu, Yan; Zuo, Fengli; Wang, Huiling; Jing, Jing; He, Xiujing

doi:10.3389/fimmu.2022.1045957

Cited by 8 publications

(4 citation statements)

References 64 publications

(82 reference statements)

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“…101 Interestingly, TAMs were found to limit the efficacy of ICIs in a mouse model of colon adenocarcinoma by capturing anti-PD-1 mAbs from the surface of PD-1 + T cells, a process dependent on the interaction between the antibody Fc-domain glycans and FcγRs on TAMs. 103 Considering TMB and PD-L1 expression as not completely reliable predictors of ICI therapy outcome in EOC, 104 intensive preclinical and clinical research is now focusing on the identification of better immune biomarkers to integrate into common diagnostic assessments and clinical management of EOC patients. For instance, a density of tumor-infiltrating CD8 + T cells predicts clinical benefit to anti-PD-L1 (avelumab) combined with pegylated liposomal doxorubicin (PLD) in OC patients.…”

Section: Clinical Relevance Of Tams In Eoc Impact Of Tams On Eoc Prog...mentioning

confidence: 99%

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Truxová

Cibula

Špíšek

et al. 2023

J Immunother Cancer

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Epithelial ovarian cancer (EOC) is among the top five causes of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant cells to the peritoneum. Despite improvements in medical therapies, particularly with the implementation of novel drugs targeting homologous recombination deficiency, the survival rates of patients with EOC remain low. Unlike other neoplasms, EOC remains relatively insensitive to immune checkpoint inhibitors, which is correlated with a tumor microenvironment (TME) characterized by poor infiltration by immune cells and active immunosuppression dominated by immune components with tumor-promoting properties, especially tumor-associated macrophages (TAMs). In recent years, TAMs have attracted interest as potential therapeutic targets by seeking to reverse the immunosuppression in the TME and enhance the clinical efficacy of immunotherapy. Here, we review the key biological features of TAMs that affect tumor progression and their relevance as potential targets for treating EOC. We especially focus on the therapies that might modulate the recruitment, polarization, survival, and functional properties of TAMs in the TME of EOC that can be harnessed to develop superior combinatorial regimens with immunotherapy for the clinical care of patients with EOC.

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Section: Clinical Relevance Of Tams In Eoc Impact Of Tams On Eoc Prog...mentioning

confidence: 99%

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Truxová

Cibula

Špíšek

et al. 2023

J Immunother Cancer

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“…Recent studies have shown that in epithelial tumors, PD-L1 could affect a variety of intrinsic mechanisms of cancer cells, such as migration, invasion, proliferation, and apoptosis [43]. In ovarian cancer, PD-L1 expression was strongly associated with poor prognosis [44], and Anti-PD-L1/PD-1 immunotherapy for ovarian cancer has attracted increasing attention [45][46][47]. Some clinical efficacy has been observed in ovarian cancer, however, most patients initially did not respond to treatment [48].…”

Section: Discussionmentioning

confidence: 99%

EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells

Shen

Jin

Fang³

et al. 2023

Cell Mol Biol Lett

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Background Fibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was highly expressed in ovarian cancer and was strongly associated with poor prognosis in patients. This study intends to further explore its interacting proteins and possible downstream signaling pathways. Method The expression of EFEMP2 was detected by RT-qPCR, ICC and western blot in 4 kinds of ovarian cancer cells with different migration and invasion ability. Cell models with strong or weak EFEMP2 expression were constructed by lentivirus transfection. The effects of the down-regulation and up-regulation of EFEMP2 on the biological behavior of ovarian cancer cells were studied through in-vitro and in-vivo functional tests. The phosphorylation pathway profiling array and KEGG database analyses identified the downstream EGFR/ERK1/2/c-Jun signaling pathway and the programmed death-1 (PD-L1) pathway enrichment. Additionally, the protein interaction between EFEMP2 and EGFR was detected by immunoprecipitation. Result EFEMP2 was positively correlated with the invasion ability of ovarian cancer cells, its down-regulation inhibited the migrative, invasive and cloning capacity of cancer cells in vitro and suppressed the tumor proliferation and intraperitoneal diffusion in vivo, while its up-regulation did the opposite. Moreover, EFEMP2 could bind to EGFR to induce PD-L1 regulation in ovarian cancer, which was caused by the activation of EGFR/ERK1/2/c-Jun signaling. Similar to EFEMP2, PD-L1 was also highly expressed in aggressive cells and had the ability to promote the invasion and metastasis of ovarian cancer cells both in vitro and in vivo, and PD-L1 upregulation was partly caused by EFEMP2 activation. Afatinib combined with trametinib had an obvious effect of inhibiting the intraperitoneal diffusion of ovarian cancer cells, especially in the group with low expression of EFEMP2, while overexpression of PD-L1 could reverse this phenomenon. Conclusion EFEMP2 could bind to EGFR to activate ERK1/2/c-Jun pathway and regulate PD-L1 expression, furthermore PD-L1 was extremely essential for EFEMP2 to promote ovarian cancer cells invasion and dissemination in vitro and in vivo. Targeted therapy against the source gene EFEMP2 is our future research direction, which may better inhibit the invasion and metastasis of ovarian cancer cells.

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“…In agreement with previous findings, MSI-H in this study was the main causative genomic finding for TMB-H induction in endometrial cancer, whereas it shared only 10% and 24% of TMB-H in cervical and ovarian cancers, respectively [ 39 , 40 ]. A low TMB-H ratio (5.0%) in ovarian cancer may be associated with limited sensitivity to ICIs [ 41 ]. A comparison between “TMB-H with MSS” and “MSI-H” in each cancer type is informative to elucidate real “driver” alterations.…”

Section: Discussionmentioning

confidence: 99%

Genomic Landscape of Endometrial, Ovarian, and Cervical Cancers in Japan from the Database in the Center for Cancer Genomics and Advanced Therapeutics

Xi,

Kage,

Ogawa

et al. 2023

Cancers

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This study aimed to comprehensively clarify the genomic landscape and its association with tumor mutational burden-high (TMB-H, ≥10 mut/Mb) and microsatellite instability-high (MSI-H) in endometrial, cervical, and ovarian cancers. We obtained genomic datasets of a comprehensive genomic profiling test, FoundationOne® CDx, with clinical information using the “Center for Cancer Genomics and Advanced Therapeutics” (C-CAT) database in Japan. Patients can undergo the tests only after standardized treatments under universal health insurance coverage. Endometrial cancers were characterized by a high frequency of TMB-H and MSI-H, especially in endometrioid carcinomas. The lower ratio of POLE exonuclease mutations and the higher ratio of TP53 mutations compared to previous reports suggested the prognostic effects of the molecular subtypes. Among the 839 cervical cancer samples, frequent mutations of KRAS, TP53, PIK3CA, STK11, CDKN2A, and ERBB2 were observed in adenocarcinomas, whereas the ratio of TMB-H was significantly higher in squamous cell carcinomas. Among the 1606 ovarian cancer samples, genomic profiling of serous, clear cell, endometrioid, and mucinous carcinomas was characterized. Pathogenic mutations in the POLE exonuclease domain were associated with high TMB, and the mutation ratio was low in both cervical and ovarian cancers. The C-CAT database is useful for determining the mutational landscape of each cancer type and histological subtype. As the dataset is exclusively collected from patients after the standardized treatments, the information on “druggable” alterations highlights the unmet needs for drug development in major gynecological cancers.

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The current landscape of predictive and prognostic biomarkers for immune checkpoint blockade in ovarian cancer

Cited by 8 publications

References 64 publications

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells

Genomic Landscape of Endometrial, Ovarian, and Cervical Cancers in Japan from the Database in the Center for Cancer Genomics and Advanced Therapeutics

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