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New Target Discovered for Prostate Cancer Immunotherapy

Key findings

  • PD-L1 expression was rare in prostate tumor cells but prevalent in tumor-associated nerves, and it inversely correlated with CD8+ tumor-associated lymphocytes
  • A high density of PD-L1+ tumor-associated nerves was an independent prognostic factor for biochemical recurrence–free survival
  • Combination immunotherapy regimens that target both neural PD-L1+ and tumor-associated lymphocytes in patients with prostate cancer may be an effective therapeutic strategy

In clinical trials, patients with advanced prostate cancer have shown overwhelming resistance to nivolumab, a checkpoint inhibitor therapy that targets programmed cell death protein 1 (PD-1). This may be attributable to low expression of programmed death ligand 1 (PD-L1) on prostate tumor cells. Complicating matters, though, patients with other cancer types who are positive for PD-L1 do not necessarily respond well to anti-PD-1/PD-L1 agents.

Previous studies have found that the number of tumor-infiltrating immune cells and the level of PD-L1 expression in the tumor microenvironment may help predict response to anti-PD-L1 therapy. Additional testing has shown definitively that PD-L1 on nontumor cells plays a role in immunosuppression.

Extending this research, Chin-Lee Wu, MD, PhD, associate pathologist and director of Genitourinary Pathology Services at Massachusetts General Hospital, and colleagues are the first to demonstrate that PD-L1 expression on tumor-associated nerves is highly prevalent in patients with prostate cancer. Their findings, published in the International Journal of Cancer, identify PD-L1+ nerves as a potentially important new target for checkpoint inhibitor therapy in prostate cancer.

Dr. Wu's team studied tumor samples from 73 consecutive patients with regionally localized prostate cancer who were treated at Mass General between 2001 and 2004.

Expression of PD-L1

Using an immunohistochemical assay, the researchers discovered that PD-L1 was prevalent in the prostate tumor microenvironment but rarely found on prostate cancer cells. Specifically, PD-L1 was expressed in tumor cells in only one case of primary prostate cancer. In contrast, in 95% of cases, PD-L1 was observed in the nerve branches of the tumor-associated stroma.

Furthermore, in both the tumor and peritumor area, the researchers observed co-immunoreactivity of PD-L1 with pan-neuron marker protein gene product 9.5. This finding lends further support to the idea that nerves contribute to an immunosuppressive tumor microenvironment. 

T Cells in the Tumor Microenvironment

The tumor microenvironment contained FoxP3+ T cells in 75% of cases, CD3+ cells in 98% and CD8+ cytotoxic cells in 100%. FoxP3 is an excellent marker of regulatory T cells that can inactivate CD8+ cells and suppress immune function.

The density of PD-L1+ tumor-associated nerves was inversely and significantly correlated with the density of CD8+ tumor-associated lymphocytes. In addition, prostate tumors with a higher density of PD-L1+ tumor-associated nerves had significantly less infiltration of CD8+ tumor-associated lymphocytes.

Considered together, these findings suggest that PD-L1+ nerves in primary prostate tumors may negatively manipulate the infiltration of CD8+ cells.

Correlations with Clinicopathological Features

Patients who had a high density of PD-L1+ tumor-associated nerves were significantly more likely than others to have a biochemical recurrence of prostate cancer (P = .048). There was a trend for high density to be associated with a higher Gleason score (P = .068).

Prostate cancer is known to be a neurotropic cancer in which cancer cells invade neural tissue. That perineural invasion is believed to be responsible for most extracapsular spread of prostate cancer. In this study, there was a trend for high density of PD-L1+ tumor-associated nerves to be associated with greater perineural invasion (P = .075).

PD-L1+ Tumor-Associated Nerves as a Prognostic Feature

Kaplan-Meier survival analysis demonstrated that a high density of PD-L1+ tumor-associated nerves was associated with reduced biochemical recurrence-free survival (P = .02). On multivariate analysis, the density of PD-L1+ nerves remained a significant prognostic factor.

These findings illustrate the therapeutic potential for the development of combination immunotherapy regimens that will target both neural PD-L1+ and tumor-associated lymphocytes in patients with prostate cancer.

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