Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance.
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.
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
A M
AM
Martin
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
T R
TR
Nirschl
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
C J
CJ
Nirschl
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
B J
BJ
Francica
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
C M
CM
Kochel
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
A
A
van Bokhoven
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
A K
AK
Meeker
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
M S
MS
Lucia
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
R A
RA
Anders
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
A M
AM
DeMarzo
Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
C G
CG
Drake
D056704:Adaptive Immunity / Q000235:genetics; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014105:Tosyl Compounds / Q000494:pharmacology; D015854:Up-Regulation
D000813:Anilides; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D015415:Biomarkers; D009570:Nitriles; D014105:Tosyl Compounds; D007371:Interferon-gamma; C053541:bicalutamide; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human