PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials
Summary This study evaluated the expression of PD‐L1 in immunotherapy‐naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and correlate PD‐L1 status with clinicopathologic characteristics and outcome. PD‐L1 expression was assessed by immunohistochemistry in 58 patie...
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| Published in | Pigment cell and melanoma research Vol. 28; no. 3; pp. 245 - 253 |
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| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Blackwell Publishing Ltd
01.05.2015
Wiley Subscription Services, Inc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1755-1471 1755-148X 1755-148X |
| DOI | 10.1111/pcmr.12340 |
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| Abstract | Summary
This study evaluated the expression of PD‐L1 in immunotherapy‐naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and correlate PD‐L1 status with clinicopathologic characteristics and outcome. PD‐L1 expression was assessed by immunohistochemistry in 58 patients (43 primary tumors, 96 metastases). Seventy‐two percent of patients had at least one specimen expressing PD‐L1 in ≥1% of tumor cells. Median positive tumor cell count overall was low (8% in nonzero specimens). PD‐L1 expression was frequently discordant between primary tumors and metastases and between intrapatient metastases, such that 23/46 longitudinal patient specimens were discordant. PD‐L1 was associated with higher TIL grade but not with other known prognostic features. There was a positive univariate association between PD‐L1 expression in locoregional metastases and melanoma‐specific survival, but the effect was not observed for primary melanoma. In locoregional lymph node metastasis, PD‐L1+/TIL+ patients had the best outcome, and PD‐L1+/TIL− patients had poor outcome. |
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| AbstractList | Summary
This study evaluated the expression of PD‐L1 in immunotherapy‐naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and correlate PD‐L1 status with clinicopathologic characteristics and outcome. PD‐L1 expression was assessed by immunohistochemistry in 58 patients (43 primary tumors, 96 metastases). Seventy‐two percent of patients had at least one specimen expressing PD‐L1 in ≥1% of tumor cells. Median positive tumor cell count overall was low (8% in nonzero specimens). PD‐L1 expression was frequently discordant between primary tumors and metastases and between intrapatient metastases, such that 23/46 longitudinal patient specimens were discordant. PD‐L1 was associated with higher TIL grade but not with other known prognostic features. There was a positive univariate association between PD‐L1 expression in locoregional metastases and melanoma‐specific survival, but the effect was not observed for primary melanoma. In locoregional lymph node metastasis, PD‐L1+/TIL+ patients had the best outcome, and PD‐L1+/TIL− patients had poor outcome. This study evaluated the expression of PD-L1 in immunotherapy-naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and correlate PD-L1 status with clinicopathologic characteristics and outcome. PD-L1 expression was assessed by immunohistochemistry in 58 patients (43 primary tumors, 96 metastases). Seventy-two percent of patients had at least one specimen expressing PD-L1 in ≥ 1% of tumor cells. Median positive tumor cell count overall was low (8% in nonzero specimens). PD-L1 expression was frequently discordant between primary tumors and metastases and between intrapatient metastases, such that 23/46 longitudinal patient specimens were discordant. PD-L1 was associated with higher TIL grade but not with other known prognostic features. There was a positive univariate association between PD-L1 expression in locoregional metastases and melanoma-specific survival, but the effect was not observed for primary melanoma. In locoregional lymph node metastasis, PD-L1+/TIL+ patients had the best outcome, and PD-L1+/TIL- patients had poor outcome.This study evaluated the expression of PD-L1 in immunotherapy-naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and correlate PD-L1 status with clinicopathologic characteristics and outcome. PD-L1 expression was assessed by immunohistochemistry in 58 patients (43 primary tumors, 96 metastases). Seventy-two percent of patients had at least one specimen expressing PD-L1 in ≥ 1% of tumor cells. Median positive tumor cell count overall was low (8% in nonzero specimens). PD-L1 expression was frequently discordant between primary tumors and metastases and between intrapatient metastases, such that 23/46 longitudinal patient specimens were discordant. PD-L1 was associated with higher TIL grade but not with other known prognostic features. There was a positive univariate association between PD-L1 expression in locoregional metastases and melanoma-specific survival, but the effect was not observed for primary melanoma. In locoregional lymph node metastasis, PD-L1+/TIL+ patients had the best outcome, and PD-L1+/TIL- patients had poor outcome. Summary This study evaluated the expression of PD-L1 in immunotherapy-naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and correlate PD-L1 status with clinicopathologic characteristics and outcome. PD-L1 expression was assessed by immunohistochemistry in 58 patients (43 primary tumors, 96 metastases). Seventy-two percent of patients had at least one specimen expressing PD-L1 in ≥1% of tumor cells. Median positive tumor cell count overall was low (8% in nonzero specimens). PD-L1 expression was frequently discordant between primary tumors and metastases and between intrapatient metastases, such that 23/46 longitudinal patient specimens were discordant. PD-L1 was associated with higher TIL grade but not with other known prognostic features. There was a positive univariate association between PD-L1 expression in locoregional metastases and melanoma-specific survival, but the effect was not observed for primary melanoma. In locoregional lymph node metastasis, PD-L1+/TIL+ patients had the best outcome, and PD-L1+/TIL- patients had poor outcome. This study evaluated the expression of PD-L1 in immunotherapy-naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and correlate PD-L1 status with clinicopathologic characteristics and outcome. PD-L1 expression was assessed by immunohistochemistry in 58 patients (43 primary tumors, 96 metastases). Seventy-two percent of patients had at least one specimen expressing PD-L1 in ≥ 1% of tumor cells. Median positive tumor cell count overall was low (8% in nonzero specimens). PD-L1 expression was frequently discordant between primary tumors and metastases and between intrapatient metastases, such that 23/46 longitudinal patient specimens were discordant. PD-L1 was associated with higher TIL grade but not with other known prognostic features. There was a positive univariate association between PD-L1 expression in locoregional metastases and melanoma-specific survival, but the effect was not observed for primary melanoma. In locoregional lymph node metastasis, PD-L1+/TIL+ patients had the best outcome, and PD-L1+/TIL- patients had poor outcome. |
| Author | Madore, Jason Vilain, Ricardo E. Thompson, John F. Hersey, Peter Yearley, Jennifer H. Kefford, Richard F. Wilmott, James S. Scolyer, Richard A. Menzies, Alexander M. Hyman, Jessica Kakavand, Hojabr Long, Georgina V. |
| Author_xml | – sequence: 1 givenname: Jason surname: Madore fullname: Madore, Jason organization: Melanoma Institute Australia, Sydney, NSW, Australia – sequence: 2 givenname: Ricardo E. surname: Vilain fullname: Vilain, Ricardo E. organization: Melanoma Institute Australia, Sydney, NSW, Australia – sequence: 3 givenname: Alexander M. surname: Menzies fullname: Menzies, Alexander M. organization: Melanoma Institute Australia, Sydney, NSW, Australia – sequence: 4 givenname: Hojabr surname: Kakavand fullname: Kakavand, Hojabr organization: Melanoma Institute Australia, Sydney, NSW, Australia – sequence: 5 givenname: James S. surname: Wilmott fullname: Wilmott, James S. organization: Melanoma Institute Australia, Sydney, NSW, Australia – sequence: 6 givenname: Jessica surname: Hyman fullname: Hyman, Jessica organization: Melanoma Institute Australia, NSW, Sydney, Australia – sequence: 7 givenname: Jennifer H. surname: Yearley fullname: Yearley, Jennifer H. organization: Merck & Co., Inc., Whitehouse Station, NJ, USA – sequence: 8 givenname: Richard F. surname: Kefford fullname: Kefford, Richard F. organization: Melanoma Institute Australia, Sydney, NSW, Australia – sequence: 9 givenname: John F. surname: Thompson fullname: Thompson, John F. organization: Melanoma Institute Australia, Sydney, NSW, Australia – sequence: 10 givenname: Georgina V. surname: Long fullname: Long, Georgina V. organization: Melanoma Institute Australia, Sydney, NSW, Australia – sequence: 11 givenname: Peter surname: Hersey fullname: Hersey, Peter organization: Melanoma Institute Australia, Sydney, NSW, Australia – sequence: 12 givenname: Richard A. surname: Scolyer fullname: Scolyer, Richard A. email: richard.scolyer@melanoma.org.au organization: Melanoma Institute Australia, Sydney, NSW, Australia |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25477049$$D View this record in MEDLINE/PubMed |
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| Copyright | 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Copyright © 2015 John Wiley & Sons A/S |
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| Keywords | pathology metastasis immunotherapy PD-L1 diagnosis melanoma biomarker PD-1 prognosis heterogeneity |
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| PublicationTitle | Pigment cell and melanoma research |
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| References_xml | – reference: Hino, R., Kabashima, K., Kato, Y., Yagi, H., Nakamura, M., Honjo, T., Okazaki, T., and Tokura, Y. (2010). Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116, 1757-1766. – reference: Hamid, O., Robert, C., Daud, A. et al. (2013a). Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134-144. – reference: Hamid, O., Sosman, J.A., Lawrence, D.P. et al. (2013b). Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). ASCO Meet. Abstr. 31, 9010. – reference: Daud, A.I., Hamid, O., Ribas, A. et al. (2014). Antitumor Activity of the Anti-PD1 Monoclonal Antibody MK-3475 in Melanoma (MEL): Correlation of Tumor PD-L1 Expression with Outcome. (San Diego: AACR). – reference: Lee, S.J., Jang, B.C., Lee, S.W. et al. (2006). Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274). FEBS Lett. 580, 755-762. – reference: IBM Corp (2013). IBM SPSS Statistics for Windows, Version 22.0. (Armonk, NY: IBM Corp). – reference: Frederick, D.T., Piris, A., Cogdill, A.P. et al. (2013). BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225-1231. – reference: Keir, M.E., Liang, S.C., Guleria, I., Latchman, Y.E., Qipo, A., Albacker, L.A., Koulmanda, M., Freeman, G.J., Sayegh, M.H., and Sharpe, A.H. (2006). Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med. 203, 883-895. – reference: Taube, J.M., Klein, A.P., Brahmer, J.R., Xu, H., Pan, X., Kim, J.H., Chen, L., Pardoll, D.M., Topalian, S.L., and Anders, R.A. (2014). Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064-5074. – reference: Taube, J.M., Anders, R.A., Young, G.D. et al. (2012). Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra37. – reference: Budczies, J., Klauschen, F., Sinn, B.V., Gyorffy, B., Schmitt, W.D., Darb-Esfahani, S., and Denkert, C. (2012). Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS One 7, e51862. – reference: Blank, C., Brown, I., Peterson, A.C., Spiotto, M., Iwai, Y., Honjo, T., and Gajewski, T.F. (2004). PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 64, 1140-1145. – reference: Murali, R., Brown, P.T., Kefford, R.F., Scolyer, R.A., Thompson, J.F., Atkins, M.B., and Long, G.V. (2012). Number of primary melanomas is an independent predictor of survival in patients with metastatic melanoma. Cancer 118, 4519-4529. – reference: Brahmer, J.R., Tykodi, S.S., Chow, L.Q. et al. (2012). Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455-2465. – reference: Pardoll, D.M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264. – reference: Spranger, S., Spaapen, R.M., Zha, Y., Williams, J., Meng, Y., Ha, T.T., and Gajewski, T.F. (2013). Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci. Transl. Med. 5, 200ra116. – reference: Topalian, S., Sznol, M., Brahmer, J. et al. (2013). 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This study evaluated the expression of PD‐L1 in immunotherapy‐naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and... This study evaluated the expression of PD-L1 in immunotherapy-naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and... Summary This study evaluated the expression of PD-L1 in immunotherapy-naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and... |
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| SubjectTerms | B7-H1 Antigen - metabolism biomarker Clinical Trials as Topic diagnosis Female Genetic Heterogeneity Heterogeneity Humans Immunohistochemistry Immunotherapy Lymphocytes, Tumor-Infiltrating - immunology Male Medical research Melanoma Melanoma - immunology Melanoma - metabolism Melanoma - pathology Metastasis Middle Aged Neoplasm Grading Neoplasm Metastasis pathology PD-1 PD-L1 Prognosis Skin Neoplasms - immunology Skin Neoplasms - metabolism Skin Neoplasms - pathology Survival Analysis Tumors |
| Title | PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials |
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