Journal
AMERICAN JOURNAL OF CANCER RESEARCH
Volume 12, Issue 1, Pages 123-137Publisher
E-CENTURY PUBLISHING CORP
Keywords
Immune checkpoint; PD-L1; glycosylation; atezolizumab; Tecentriq; triple-negative breast cancer
Categories
Funding
- Ministry of Health and Welfare, Taiwan [MOHW109-TDU-B-212-010001, MOHW107-TDU-B-212-112015]
- Kaohsiung Medical University Hospital [KM-UH-DK(C)110005, KM-UH-DK-109001, KM-UH108-8R36, KM-UH-DK-109003-2, KM-UH-DK-109003-3, KM-UH109-9R37]
- KMU-KMUH Co-Project of Key Research [KMU-DK-109003-1]
- Ministry of Science and Technology, Taiwan [110-2320-B-037-006-, 110-2628-B-037-011-, 110-2321-B-037-002-, 109-2314-B-037-019, 109-2314-B-037-132-, 109-2314-B-037-036-MY3]
- Kaohsiung Medical University Research Center Grant [KMU-KI110001, KMU-TC109A03, KMU-TC10-8A03-6, KMU-TC109B05]
- MOST [110-2639-B-039-001-ASP]
- Breast Cancer Research Fund [BRCF-21-070]
- Drug Development Center of the China Medical University by the Ministry of Education in Taiwan
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This study found that de-glycosylation of tumor cell surface PD-L1 staining is significantly correlated with clinical response in atezolizumab treatment for breast cancer. These findings suggest that de-glycosylation procedure may serve as a patient stratification strategy and should be further explored.
The atezolizumab (Tecentriq), a humanized antibody against human programmed death ligand 1 (PD-L1), combined with nab-paclitaxel was granted with accelerated approval to treat unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) due to the encouraging positive results of the phase 3 IMpassion130 trial using PD-L1 biomarker from immune cells to stratify patients. However, the post-market study IMpassion131 did not support the original observation, resulting in the voluntary withdrawal of atezolizumab from the indication in breast cancer by Genentech in 2021. Emerging evidence has revealed a high frequency of false negative result using the standard immunohistochemical (IHC) staining due to heavy glycosylation of PD-L1. The removal of glycosylation prevents from the false negative staining, enabling more accurate assessment of PD-L1 levels and improving prediction for response to immune checkpoint therapy. In the present study, the natural and de-glycosylated PD-L1 expression in tumor and immune cells from nine TNBC patients were analyzed by using clone 28-8 monoclonal antibody to correlate with treatment outcome. Our results demonstrate that: (1) Removal of the glycosylation indeed enhances the detection of PD-L1 by IHC staining, (2) The PD-L1 levels on tumor cell surface after removal of the glycosylation correlates well with clinical responses for atezolizumab treatment; (3) The criteria used in the IMpassion130 and IMpassion131 trials which scored the natural PD-L1 in the immune cells failed to correlate with the clinical response. Taken together, tumor cell surface staining of PD-L1 with de-glycosylation has a significant correlation with the clinical response for atezolizumab treatment, suggesting that treatment of atezolizumab may be worthy of further consideration with de-glycosylation procedure as a patient stratification strategy. A larger cohort to validate this important issue is warranted to ensure right patient population who could benefit from the existing FDA-approved drugs.
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