TY - JOUR
T1 - Paucity of PD-L1 expression in prostate cancer
T2 - Innate and adaptive immune resistance
AU - Martin, A. M.
AU - Nirschl, T. R.
AU - Nirschl, C. J.
AU - Francica, B. J.
AU - Kochel, C. M.
AU - Van Bokhoven, A.
AU - Meeker, A. K.
AU - Lucia, M. S.
AU - Anders, R. A.
AU - Demarzo, A. M.
AU - Drake, C. G.
N1 - Funding Information:
CGD has consulted for Amplimmune, Bristol Myers Squibb (BMS), Merck and Roche-Genentech, all of whom have either anti-PD-1 or anti-PD-L1 reagents in various stages of clinical development. In addition, Drs Anders and Drake have received sponsored research funding from BMS. The first author Dr Martin has no conflict of interest to declare. All the other authors declare no conflict of interest.
Funding Information:
We thank John T Isaacs, PhD, for donating the human prostate cancer cell lines for this study and Susan Dalrymple, BS, for instructing us on maintaining them. We also thank Olesya Chornoguz, PhD, for instruction regarding western blotting for phosphor-AKT. This work was funded by CGD: National Institutes of Health R01 CA127153, the Patrick C Walsh Fund, the One-in-Six Foundation, the Koch Foundation and the Prostate Cancer Foundation. AMD is the Virginia and Warren Schwerin Scholar and is supported by 1P50CA58236-15, the Patrick C Walsh Fund and the Prostate Cancer Foundation. AvB and MSL: NIH P30CA046934. This work was also supported by the NIH P30 CA006973 to the Johns Hopkins Sidney Kimmel Cancer Center.
Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - BACKGROUND:Primary prostate cancers are infiltrated with programmed death-1 (PD-1) expressing CD8+ T-cells. However, in early clinical trials, men with metastatic castrate-resistant prostate cancer did not respond to PD-1 blockade as a monotherapy. One explanation for this unresponsiveness could be that prostate tumors generally do not express programmed death ligand-1 (PD-L1), the primary ligand for PD-1. However, lack of PD-L1 expression in prostate cancer would be surprising, given that phosphatase and tensin homolog (PTEN) loss is relatively common in prostate cancer and several studies have shown that PTEN loss correlates with PD-L1 upregulation - constituting a mechanism of innate immune resistance. This study tested whether prostate cancer cells were capable of expressing PD-L1, and whether the rare PD-L1 expression that occurs in human specimens correlates with PTEN loss.METHODS:Human prostate cancer cell lines were evaluated for PD-L1 expression and loss of PTEN by flow cytometry and western blotting, respectively. Immunohistochemical (IHC) staining for PTEN was correlated with PD-L1 IHC using a series of resected human prostate cancer samples.RESULTS:In vitro, many prostate cancer cell lines upregulated PD-L1 expression in response to inflammatory cytokines, consistent with adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not associated with PTEN loss.CONCLUSIONS:These studies show that some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates antitumor immune responses in this disease.
AB - BACKGROUND:Primary prostate cancers are infiltrated with programmed death-1 (PD-1) expressing CD8+ T-cells. However, in early clinical trials, men with metastatic castrate-resistant prostate cancer did not respond to PD-1 blockade as a monotherapy. One explanation for this unresponsiveness could be that prostate tumors generally do not express programmed death ligand-1 (PD-L1), the primary ligand for PD-1. However, lack of PD-L1 expression in prostate cancer would be surprising, given that phosphatase and tensin homolog (PTEN) loss is relatively common in prostate cancer and several studies have shown that PTEN loss correlates with PD-L1 upregulation - constituting a mechanism of innate immune resistance. This study tested whether prostate cancer cells were capable of expressing PD-L1, and whether the rare PD-L1 expression that occurs in human specimens correlates with PTEN loss.METHODS:Human prostate cancer cell lines were evaluated for PD-L1 expression and loss of PTEN by flow cytometry and western blotting, respectively. Immunohistochemical (IHC) staining for PTEN was correlated with PD-L1 IHC using a series of resected human prostate cancer samples.RESULTS:In vitro, many prostate cancer cell lines upregulated PD-L1 expression in response to inflammatory cytokines, consistent with adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not associated with PTEN loss.CONCLUSIONS:These studies show that some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates antitumor immune responses in this disease.
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U2 - 10.1038/pcan.2015.39
DO - 10.1038/pcan.2015.39
M3 - Article
C2 - 26260996
AN - SCOPUS:84947031227
SN - 1365-7852
VL - 18
SP - 325
EP - 332
JO - Prostate Cancer and Prostatic Diseases
JF - Prostate Cancer and Prostatic Diseases
IS - 4
ER -
