Cell membrane and nuclear expression of programmed death ligand-1 in prostate needle biopsy tissue in prostate cancer patients undergoing primary radiation therapy

Bisagni

et al. 2021

IJMS

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).

Section: Experimental Studies Tested Various Types Of Treatment On Pc-cell Lines To Evaluate Their Effect On Pd-l1 Expression/regulationsupporting

confidence: 65%

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models)

Bisagni

et al. 2021

IJMS

“…Haffner et al (n = 508; p = 0.08) [66] and Calagua et al (n = 351; p = 0.013 for 1% cut-off of PD-L1 positivity, GG4-5 vs. GG1-3) [75] also found increased PD-L1 expression in highgrade tumors. In the study of Shim et al (n = 171) [12], GG positively correlated with membranous PD-L1 expression, being inversely associated with nuclear PD-L1 positivity; there was intratumoral heterogeneity in PD-L1 expression among different GSs, and no significant correlation between membranous and nuclear PD-L1 expression was found.…”

Section: Pd-l1 Expression Andmentioning

confidence: 84%

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 2: Clinic–Pathologic Correlations

Bonacini

et al. 2021

Cells

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic–pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

“…We found that 29% of acinar PCs, 7% of ductal PCs, and 46% of neuroendocrine carcinomas or tumors were classified as PD-L1-positive by immunohistochemical analysis on tumor tissue, despite these results may be influenced by some selection biases [8,9,[11][12][13]17,21,27,29,32,[35][36][37][38][39][41][42][43][44][50][51][52][53][54][55]57,[59][60][61][62]66,67,74,75,[77][78][79][83][84][85]89,90,[92][93][94][98][99][100]111,…”

Section: Discussionmentioning

confidence: 99%

“…Based on the results of our review, the positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The positivity rate of clone 22C3 (the most used to assess eligibility for administration of pembrolizumab) was 11% after excluding cases with a CPS score of ≥1 (as it was unclear if tumor cells resulted positive), 41% after including those cases, and 78% only considering the cases scored as CPS ≥1 [9,12,13,21,27,32,35,51,77,80,83,90,154].…”

Section: Discussionmentioning

confidence: 99%

“…When data were available and analyzable, the PD-L1 positivity rate of non-TMA specimens was 50% (240/483) for biopsies [9,11,12,21,32,62,90] and 41% (587/1427) for RPs [18,38,[42][43][44]57,61,75,79,94]. In TMA series (variably including RPs, biopsies, TURPs, metastases, autopsies), the expression rate was lower (258/1728, 15%) [27,29,35,39,41,53,66,67,74,78,83,92,112,120].…”

Section: Pd-l1 Immunohistochemical Expression In Different Specimen-types Of Prostatic Adenocarcinomamentioning

confidence: 99%

See 1 more Smart Citation

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 1: Focus on Immunohistochemical Results with Discussion of Pre-Analytical and Interpretation Variables

Bonacini

et al. 2021

Cells

Immunotherapy targeting the PD-1–PD-L1 axis yielded good results in treating different immunologically ‘‘hot’’ tumors. A phase II study revealed good therapeutic activity of pembrolizumab in selected prostatic carcinoma (PC)-patients. We performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables. Interestingly, 29% acinar PCs, 7% ductal PCs, and 46% neuroendocrine carcinomas/tumors were PD-L1+ on immunohistochemistry. Different scoring methods or cut-off criteria were applied on variable specimen-types, evaluating tumors showing different clinic-pathologic features. The positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The most tested clone was E1L3N, followed by 22C3 (most used for pembrolizumab eligibility), SP263, SP142, and 28-8, which gave the positivity rates of 35%, 11–41% (depending on different scoring systems), 6%, 3%, and 15%, respectively. Other clones were tested in <200 cases. The PD-L1 positivity rate was usually higher in tumors than benign tissues. It was higher in non-tissue microarray specimens (41–50% vs. 15%), as PC cells frequently showed heterogenous or focal PD-L1-staining. PD-L1 was expressed by immune or stromal cells in 12% and 69% cases, respectively. Tumor heterogeneity, inter-institutional preanalytics, and inter-observer interpretation variability may account for result biases.