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. 2015 Dec;18(4):325-32.
doi: 10.1038/pcan.2015.39. Epub 2015 Aug 11.

Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance

A M Martin  1 , T R Nirschl  1 , C J Nirschl  1 , B J Francica  1 , C M Kochel  1 , A van Bokhoven  1 , A K Meeker  1 , M S Lucia  1 , R A Anders  1 , A M DeMarzo  1 , C G Drake  1
Affiliations

Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance

A M Martin et al. Prostate Cancer Prostatic Dis. 2015 Dec.

Abstract

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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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare competing financial interests. Charles G. Drake 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. Allison M. Martin has no conflicts of interest to declare.

Figures

FIGURE 1
FIGURE 1. Human Prostate Cancer Cell Lines Display Varying Expression of PD-L1 in Response to IFN-γ
Histograms representing PD-L1 surface expression as detected by flow cytometry in human prostate cancer cell lines with and without exposure to IFN-γ. Open histograms represent cells stained with an isotype IgG1 antibody tagged with a matching PE fluorochrome. Shaded histograms represent PD-L1. Quantitative measurements reflect mean fluorescence index. LNCaP does not express PD-L1 at rest or in response to IFN-γ. DU145 expresses PD-L1 at rest and has little response to IFN-γ indicating an innate immune resistance phenotype. PC3 expresses PD-L1 at rest but robustly up-regulates this expression in response to IFN-γ displaying a more classic adaptive immune resistance phenotype.
FIGURE 2
FIGURE 2. Human Prostate Cancer Cell Lines Display No Change in PD-L1 Expression in Response to Bicalutamide
Histograms representing PD-L1 surface expression as detected by flow cytometry in human prostate cancer cell lines with and without exposure to bicalutamide. Open histograms represent cells stained with an isotype IgG1 antibody tagged with a matching PE fluorochrome. Shaded histograms represent PD-L1. Quantitative measurements reflect mean fluorescence index. LNCaP, DU145, and PC3 displayed no changes in PD-L1 expression upon exposure to bicalutamide.
FIGURE 3
FIGURE 3. Activation of the PI3K/MAPK Pathway Does Not Correlate with PD-L1 Expression in Human Prostate Cancer Cell Lines
Western Blot quantitating PTEN and p-AKT protein in CWR22Rv1, LAPC-4, PC3, DU145, and E006AA with and without exposure to IFN-γ.
FIGURE 4
FIGURE 4. Loss of PTEN Does Not Correlate with PD-L1 Expression in Resected Primary Prostate Carcinomas
PD-L1 and PTEN staining in tumor lesions from two different patients. A. Case number 8 showing focally positive PD-L1 area. Arrow indicates positive tumor cell staining which is predominantly on the plasma membrane. B, similar region from adjacent section of case number 8 showing intact PTEN staining in all tumor cells (arrow shows a group of tumor cells with intact PTEN staining). C, case number 9 showing negative staining for PDL1 in all tumor cells (arrow shows tumor cells without PD-L1 staining). D, adjacent region showing PTEN loss in nearly all of the tumor cells (arrow shows tumor cells with negative PTEN staining; arrowhead shows stromal element with strongly positive PTEN staining). All images taken at 100 X original magnification.
FIGURE 5
FIGURE 5. PD-L1 Is Expressed on Infiltrating Inflammatory Cells
Surface expression of PD-L1 demonstrated by macrophages (arrows) infiltrating the lumen of a benign gland from prostatectomy Case number 1. Image taken at 200 X original magnification.
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