Characterisation of tumour-infiltrating lymphocytes in benign and malignant prostate tissues
AuthorWoon, Teck Sing
AffiliationSurgery (Austin & Northern Health)
Access StatusOpen Access
© 2018 Dr. Teck Sing Woon
Over the past decade, we have seen a significant advancement in the treatment of metastatic castrate-resistant prostate cancer (PC). Cancer immunotherapy is now a reality, but the information on tumour infiltrating lymphocytes (TILs) in human prostate tissues is still limited. This project aims to evaluate and compare T cell characteristics in blood and tissues from patients with benign and malignant prostate conditions using flow-cytometry. Patients with benign prostatic hyperplasia (BPH) and normal prostate (NP) were used as controls and compared with patients with PC. We also examined the effects of androgen deprivation therapy (ADT) on systemic immune responses and immune regulation in patients with advanced/metastatic PC. The T cell characteristics evaluated were: (1) The proportion of regulatory T cell (Treg) and CD8/Treg ratio; (2) The percentage of activated cytotoxic lymphocytes (CTLs); and (3) The T cell maturation status. We found that the proportion of Treg in PC tissue was 5.6%, consistent with other studies. We did not find any differences in the proportion of Treg or CD8/Treg ratio in tissues for the three patient groups. When evaluating PC involved vs PC non-involved tissues, as an internal control comparison, PC involved tissues were found to have a higher percentage of Treg (6.89% vs 4.15%, p-value of 0.045) and a lower CD8+/Treg ratio (54 vs 119, p-value of 0.0032) than PC non-involved tissues. Despite a small number of 6 cases, the differences were statistically significant. These findings support the hypothesis of local immunosuppression in PC-involved tissues, and that such immunosuppression might be compartmentalised even to the level of specific lobes of the prostate. In this compartmentalised environment, PC cells can evade and survive the immune system’s defences. This study did not find any correlation between Gleason scores and the percentage of Treg in the CD4+ T cell subset or the CD8/Treg ratio either in PBMC or PC tissue. In the PC group, the same percentages of CD8+ T cells were found in both tissues and peripheral blood for majority of the patients. This showed that CD8+ T cells were not expelled or excluded from the tumour micro-environments, therefore the PC tissues were of the T-inflamed phenotype. When comparing tissue with PBMC, the levels of Treg are two times higher in tissues (both benign and malignant) than in peripheral blood. This could be a phenomenon across all tissue types and not exclusive to the prostate. Their role presumably is to maintain peripheral tolerance. We also found that the percentage of activated CD8+ T cells was ~20 times higher in tissues than in blood, regardless of the tissue type. Again, it is possible that this is not exclusive to the prostate. Profiling the immune infiltrates of other tissue types will help to clarify this. Using PCR, we have assessed the cytokine profiles in benign and malignant prostate tissues, and there were no significant differences in the levels of IFNγ, TNFα, TGFβ and IL-10 expressions. Our assays did not detect IL-4, IL-5 and IL-13 in any sample. To assess the impact of ADT on T cells, we evaluated the T cell characteristics in peripheral blood of 15 patients before ADT, at 3 months and then at 9-12 months after ADT. There was a significant reduction in the percentage of Treg by 15% after 3 months of ADT. This suggested there was an initial reduction in immune suppression during the first year of ADT. There was a significant decreased in the proportion of naïve T after 9-12 months of ADT. This suggested naïve T cells might have developed into other more mature T cell subsets after ADT.
Keywordsprostate cancer; cancer immunology; androgen deprivation therapy; tissue infiltrating lymphocyte
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