Targeting the Programmed Cell Death-1 Pathway in Genitourinary Tumors: Current Progress and Future Perspectives
Steven A Mann1, Antonio Lopez-Beltran2, Francesco Massari3
1Departments of Pathology, Indiana University School of Medicine, Indianapolis. United States.
Background:
Immune checkpoint inhibitors have revolutionized the treatment of many malignancies with over a dozen new United States Food and Drug Administration (FDA) approvals in the past six years. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors, gathering prognostic and predictive information about FDA-indicated tumors is prudent.
Method:
PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including Renal Cell Carcinoma (RCC) and urothelial carcinoma. Each FDAapproved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. The majority of PD-1/PDL1 inhibitor clinical trials use proprietary IHC antibodies with undefined validation data. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers. There is a wealth of recent publications using antibody clones to characterize tumor PD-1/PD-L1 expression profiles.
Results:
PD-1 is expressed on lymphocytes. PD-L1 is expressed on both tumor cells and immune cells. IHC staining appears in membranous fashion. A cutoff of at least 5% tumor cell PD-L1 staining for positivity has worked for most studies. Caution should be observed when employing tissue microarray techniques.
Conclusion:
RCC has been the most studied of the genitourinary malignancies for PD-L1 expression. The atezolizumab- approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in urothelial carcinoma. With familiarity of the current FDA guidelines, published medical literature, and general immunohistochemical considerations, the use of immune checkpoint biomarkers can continue to flourish.
Insights
Immune checkpoint inhibitors offer potent cancer treatments but carry risks. Understanding PD-L1 expression through Immunohistochemistry (IHC) is crucial for predicting treatment response and patient outcomes in various cancers.
Area of Science:
- Oncology
- Immunology
- Pathology
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, leading to numerous FDA approvals.
- Despite their efficacy, ICIs can cause severe adverse effects, necessitating prognostic and predictive biomarker research.
Purpose of the Study:
- To review the role of PD-L1 expression as a biomarker in predicting response to PD-1/PD-L1 inhibitors.
- To highlight the importance of understanding PD-L1 Immunohistochemistry (IHC) assays and their validation.
Main Methods:
- Analysis of PD-L1 expression patterns in tumor cells and immune cells using IHC.
- Review of existing literature and FDA-approved companion diagnostic assays for PD-1/PD-L1 inhibitors.
- Consideration of staining patterns and positivity cutoffs (e.g., ≥5% tumor cell staining).
Main Results:
- PD-L1 expression on tumor and immune cells, often with membranous staining, is linked to better ICI response.
- Renal Cell Carcinoma (RCC) and urothelial carcinoma are key genitourinary malignancies studied for PD-L1 expression.
- The atezolizumab assay uniquely quantifies immune cell staining for urothelial carcinoma.
Conclusions:
- Accurate interpretation of PD-L1 IHC biomarkers is essential for optimizing ICI therapy.
- Familiarity with FDA guidelines, literature, and IHC principles supports the advancement of ICI biomarker applications.
- Further research and standardized validation of IHC assays are needed to fully leverage PD-L1 as a predictive biomarker.
