Immune content linked to aggressive PCa outcomes

The level of immune response in prostate cancer may predict a patient’s response to radiation therapy, risk of disease recurrence, and survival outcomes, according to results of a recent analysis of prostate tumors presented at the American Society for Radiation Oncology (ASTRO) annual meeting in San Diego.

“There's lots of work being done currently about the relationship between radiation and the immunotherapy,” said researcher Shuang (George) Zhao, MD, of the University of Michigan, Ann Arbor.

“This just provides another line of evidence that there's some sort of interaction and we really should be focusing on this,” added Dr. Zhao, who worked on the study with Felix Y. Feng, MD, and co-authors.

In a related finding, the tumors Dr. Zhao and co-authors evaluated had low expression of PD-L1, but high expression of PD-L2, a finding that could have important implications for the development of checkpoint inhibitors that target these ligands.

PD-L1 is the target of several checkpoint inhibitors that are approved by the FDA for other cancer types, including melanoma and non-small cell lung cancer.

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“PD-L2 seems to come out in prostate cancer as a particularly important checkpoint molecule, much more so than PD-L1,” Dr. Zhao said in an interview with Urology Times. “That (finding) is definitely really interesting, because there's so much focus on PD-L1, but there are all of these different immune checkpoint molecules, and it may not be that every single tumor type is as dependent on PD-L1 as, say, in lung cancer.”

The goal of the investigations was to help better define the “immune landscape” of localized prostate cancer, according to the researchers, who examined a total of 9,393 tumor samples from men who underwent a radical prostatectomy, including 1,567 samples obtained retrospectively and 7,826 obtained prospectively.

They measured immune content in the tumor samples using high-throughput genome-wide expression analysis, and developed an immune content score that estimates the overall immune infiltrate in the samples.

The authors grouped the samples into clusters defined by level of immune expression, and found that a higher immune content score was associated with worse outcomes, including overall survival (hazard ratio [HR]=1.3, p=.006), prostate cancer-specific survival (HR=1.5, p=.0003), freedom from disease progression (HR=1.3, p=.0002), and freedom from distant metastases (HR=1.3, p=.0006), according to data presented at ASTRO, which represented analysis of the retrospectively obtained samples only.

Next: Immune content score was prognostic primarily in patients that received post-op radiation

Interestingly, the immune content score was prognostic primarily in patients that received post-op radiation, according to the researchers.

“Radiation has been hypothesized to interact with the immune system, and there are multiple ongoing studies investigating this relationship clinically with immunotherapies,” Dr. Zhao said. “Therefore, this finding is particularly intriguing and warrants further investigation.”

Dr. Zhao and co-authors also looked at the interaction between immune and tumor cells, finding, for example, that higher levels of T-cells and macrophages were prognostic for worse distant metastasis-free survival (p<.05).

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PD-L1 in this study was not associated with outcomes. In contrast, PD-L2-a ligand that is also a binding partner of the PD-1 receptor on T-cells-was associated with worse treatment outcomes. Higher levels of PD-L2 were associated with greater likelihood of prostate cancer death (HR=1.45, p=.003), disease recurrence (HR=1.17, p=.013), and distant metastasis (HR=1.25, p=.014).

“Hopefully, PD-L2 will become a more well-studied target,” Dr. Zhao said in an interview. “Some of the PD-1 inhibitors such as pembrolizumab [KEYTRUDA] and nivolumab [OPDIVO] also theoretically would inhibit the PD-1/PD-L2 interaction.”

Dr. Zhao has received a research grant from the Prostate Cancer Foundation and travel expenses from GenomeDx Biosciences. Several of his co-authors have a financial or other relationship with one or more pharmaceutical companies.

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