PD-L1 Expression in Triple Negative Breast Cancer
By E. Mittendorf, A. Philips, Funda Meric-Bernstam, N. Qiao, Yun Wu, S. Harrington, X. Su, Ying Wang, A. González-Angulo, A. Akcakanat and 7 more. Cancer immunology research, 2014
1,170 citations recorded by the source corpus.
Using tissue microarrays containing 105 triple-negative breast cancer (TNBC) specimens, Mittendorf and colleagues show that 20% of the TNBC specimens express PD-L1, half have lost PTEN, and inhibitors of PI3K pathway decrease PD-L1 expression, providing a rationale for therapeutic targeting of PD-L1 for TNBC. Early-phase trials targeting the T-cell inhibitory molecule programmed cell death ligand 1 (PD-L1) have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple-negative breast cancer (TNBC) and to investigate the loss of PTEN as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC (n = 120) compared with non-TNBC (n = 716; P < 0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression, which was present in 19% (20 of 105) of TNBC specimens. PD-L1+ tumors had greater CD8+ T-cell infiltrate than PD-L1− tumors (688 cells/mm vs. 263 cells/mm; P < 0.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN short hairpin RNA (shRNA). PTEN knockdown led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, phosphoinositide 3-kinase (PI3K) pathway inhibition using the AKT inhibitor MK-2206 or rapamycin resulted in decreased PD-L1 expression, further linking PTEN and PI3K signaling to PD-L1 regulation. Coculture experiments were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 cell surface expression by tumor cells induced by PTEN loss led to decreased T-cell proliferation and increased apoptosis. PD-L1 is expressed in 20% of TNBCs, suggesting PD-L1 as a therapeutic target in TNBCs. Because PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may increase the antitumor adaptive immune responses. Cancer Immunol Res; 2(4); 361–70. ©2014 AACR.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/c5b1e505e825d024c846fd4f12b0bb5207383b23
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Citations in the corpus
- Regulation of PD-L1: a novel role of pro-survival signalling in cancer. (2016, result): “This was supported by observations that knockdown of PTEN resulted in up-regulation of PD-L1 that was abolished by the inhibition of Akt [16, 17].”
- Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer: A Phase 1 Study (2019, neutral): “(%) [95% CI] 5 (24) [8-47] 10 (11) [5-19] 0 [0-17] 15 (16) [10-26]”
- Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. (2016, background): “001).(20) Subsequent studies reported that PD-L1 is expressed in approximately 20% to 30% of TNBC,(20,35) is associated with infiltrating lymphocytes,(23) and correlates with higher histologic grade.”
- PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer (2023, background): “Finally, many studies have associated activated PAM signaling with increased PD-L1 expression [422, 423], and PAM inhibition has been shown to be capable of reducing PD-L1 expression in PTEN-driven breast and CRC cells [424].”
- Clinical significance of tumor-infiltrating lymphocytes in breast cancer (2016, background): “PD-L1 infiltrate has been associated with TN breast cancer and CD8+ T-cell infiltrate (Table 2) [27].”
- Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study (2017, background): “PD-L1 expression may serve as a marker of immune activity, and local immunosuppression of TILs via the PD-L1/PD-1 pathway may be an important means of tumor immune evasion [8, 14].”