Targeting PD-1/PD-L1 axis as new horizon for ovarian cancer therapy

Khatoon, Elina; Dey, Parama; Kumar, Aviral; Alqahtani, Mohammed S.; Abbas, Mohamed; Girisa, Sosmitha; Sethi, Gautam; Kunnumakkara, Ajaikumar B.

doi:10.1016/j.lfs.2022.120827

Cited by 15 publications

(9 citation statements)

References 127 publications

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“…Finally, a high infiltration of TILs and the presence or absence of exhaustion and/or activation markers is not always correlated to a good response or any response at all. An example of this is ovarian cancer where several clinical trials with immune therapy show little-to-no response to ICB, even in tumours with high densities of TILs [ 121 , 122 ].…”

Section: Introductionmentioning

confidence: 99%

Tumour-infiltrating lymphocytes: from prognosis to treatment selection

et al. 2022

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Tumour-infiltrating lymphocytes (TILs) are considered crucial in anti-tumour immunity. Accordingly, the presence of TILs contains prognostic and predictive value. In 2011, we performed a systematic review and meta-analysis on the prognostic value of TILs across cancer types. Since then, the advent of immune checkpoint blockade (ICB) has renewed interest in the analysis of TILs. In this review, we first describe how our understanding of the prognostic value of TIL has changed over the last decade. New insights on novel TIL subsets are discussed and give a broader view on the prognostic effect of TILs in cancer. Apart from prognostic value, evidence on the predictive significance of TILs in the immune therapy era are discussed, as well as new techniques, such as machine learning that strive to incorporate these predictive capacities within clinical trials.

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Section: Introductionmentioning

confidence: 99%

Tumour-infiltrating lymphocytes: from prognosis to treatment selection

et al. 2022

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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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“…[5,6] The interaction between PD-L1 and its receptor PD-1 induces negative regulatory functions, inhibiting the activation, proliferation, and cytokine secretion of T cells, which in turn facilitates immune escape of tumor cells. [7,8] Significant progress has been made in using PD-1/PD-L1-specific monoclonal antibodies like nivolumab and atezolizumab for the treatment of various cancers, including GC, non-small cell lung cancer, malignant melanoma, and urologic epithelial tumors. [6,[8][9][10][11][12] However, the long-term efficacy of PD-1/PD-L1 inhibitors is observed in only 10% to 30% of patients, necessitating accurate patient selection to enhance therapeutic efficacy.…”

Section: This Work Was Supported By the Suzhou Science And Technology...mentioning

confidence: 99%

“…[7,8] Significant progress has been made in using PD-1/PD-L1-specific monoclonal antibodies like nivolumab and atezolizumab for the treatment of various cancers, including GC, non-small cell lung cancer, malignant melanoma, and urologic epithelial tumors. [6,[8][9][10][11][12] However, the long-term efficacy of PD-1/PD-L1 inhibitors is observed in only 10% to 30% of patients, necessitating accurate patient selection to enhance therapeutic efficacy. Studies on tumors have suggested that the effectiveness of anti-PD-L1 treatment is related to the expression of PD-L1 in tumor tissues and infiltrating cells within the tumor stroma.…”

Section: This Work Was Supported By the Suzhou Science And Technology...mentioning

confidence: 99%

Expression and clinical significance of PD-L1 and infiltrated immune cells in the gastric adenocarcinoma microenvironment

Quan,

Guo,

Huang

et al. 2023

Medicine

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Programmed death-ligand 1 (PD-L1) is a crucial negative costimulatory molecule expressed on both tumor and immune cells. It binds to programmed death-1, facilitating tumor escape. Tumor-infiltrating immune cells play a vital role in this process. However, the clinical relationship between PD-L1 expression and tumor-infiltrating immune cells remains uncertain. Immunohistochemistry (IHC) was utilized to assess PD-L1 expression and TIIC markers (CD3, CD4, CD8, CD19, CD31, CD68, CD11c, CD56, and α-smooth muscle actin) in gastric adenocarcinoma tissues from 268 patients. The aim was to explore the prognostic significance of PD-L1 and the infiltration of different immune cell types. The study analyzed overall survival and the correlations between PD-L1 expression, immune cell infiltration, and clinicopathological characteristics. Among the 268 patients, 52 (19.40%) exhibited high PD-L1 expression on tumor cells (TPD-L1), while 167 (62.31%) displayed high PD-L1 expression on immune cells (IPD-L1). Patients with high IPD-L1 expression showed improved survival compared to those with low IPD-L1 expression (P = .028). High TPD-L1 expression associated with various clinicopathological features, such as larger tumor size, poorer differentiation, deeper invasion depth, and higher tumor stage. Conversely, patients with high IPD-L1 expression exhibited shallower tumor invasion and lower mortality rates. Univariate analysis indicated that superficial tumor infiltration, absence of lymph node and distant metastasis, low tumor stage, high IPD-L1 expression, and elevated CD8 and CD19 expression were associated with a reduced risk of tumor progression. Multivariate analysis revealed that patients with high IPD-L1 and CD8 expression or high TPD-L1 and low CD31 expression experienced significantly better overall survival than patients with other combinations. The findings indicate that patients with high PD-L1 expression in immune cells have a substantially improved prognosis. Additionally, the combination of PD-L1 with CD8 or CD31 expression status can serve as an indicator of prognosis in patients with gastric adenocarcinoma.

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Targeting PD-1/PD-L1 axis as new horizon for ovarian cancer therapy

Cited by 15 publications

References 127 publications

Tumour-infiltrating lymphocytes: from prognosis to treatment selection

Tumour-infiltrating lymphocytes: from prognosis to treatment selection

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

Expression and clinical significance of PD-L1 and infiltrated immune cells in the gastric adenocarcinoma microenvironment

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