Median cell densities by Grade Group (GG).

BackgroundImmunotherapy has demonstrated limited activity in prostate cancer to date. This likely reflects an immune suppressive tumor microenvironment (TME), with previous studies suggesting low PD-L1 expression and a sparse immune cell infiltrate. We aimed to further characterise the immune TME in primary prostate cancer and correlate immune subset densities with clinical outcomes.MethodsTwo distinct cohorts of patients treated with radical prostatectomy were identified, based on the development of biochemical recurrence (BCR), one subgroup with high International Society of Urological Pathologists (ISUP) grade group, recurrent disease and a second with low grade, non-recurrent disease. A prostate immunohistochemical (IHC) antibody cocktail was used to differentiate tumor and peritumoral benign tissue. Specific CD8+, CD4+, FoxP3+, CD20+ and CD68+ cell subsets were identified using IHC staining of consecutive slides. PD-L1 and CD8/PD-L1 dual staining were also performed. Cell subset densities were quantified within tumor and peritumoral regions. We used descriptive statistics to report cell subset densities and T-tests to compare groups by age, grade and the development of BCR. Univariable and multivariable logistic regression were used to analyse risk factors for BCR and the development of metastatic disease.ResultsA total of 175 patients were included, with a median age of 63 years and median pre-operative PSA of 8.2ng/ml. BCR occurred in 115 patients (66%) and 56 (32%) developed metastatic disease. CD68+ cells were the most abundant (median 648.8/mm2 intratumoral, 247.6/mm2 peritumoral), while PD-L1+ and PD-L1/CD8+ cell density was low overall (PD-L1+ median 162.4/mm2 intratumoral, 141.7/mm2 peritumoral; PD-L1/CD8+ (median 5.52/mm2 intratumoral, 3.41/mm2 peritumoral). Overall, grade group and T-stage were independently associated with BCR and metastatic disease. Higher density of peritumoral PD-L1+ cells was an independent risk factor for BCR (OR 5.33, 95%CI 1.31–21.61, p = 0.019).Although higher densities of CD8+ and CD4+ cells were observed in higher grade group 3–5 tumors, these were not associated with the development of BCR or metastasis.ConclusionsIn our cohort of prostate cancer patients who underwent radical prostatectomy, higher grade group and T-stage were independent predictors of BCR and metastasis. Despite higher grade group being associated with higher CD8+ cell density, PD-L1+ and PD-L1/CD8+ cell densities were low overall, suggesting lower T cell receptor recognition of tumor antigens. Further understanding of this phenomenon would influence development of future immunotherapeutic strategies in prostate cancer.

背景：截至目前，免疫治疗在前列腺癌治疗中显示出有限的活动性。这可能是由于免疫抑制性的肿瘤微环境（TME）所致，既往研究提示PD-L1表达水平较低，免疫细胞浸润稀疏。本研究旨在进一步对原发性前列腺癌的免疫TME进行特征描述，并关联免疫亚群密度与临床预后。方法：根据生化复发（BCR）的发展，确定了两组接受根治性前列腺切除术的患者，一组为高国际泌尿病理学家协会（ISUP）分级组，有复发疾病，另一组为低分级、非复发疾病。使用前列腺免疫组化（IHC）抗体混合物来区分肿瘤和肿瘤周围良性组织。通过连续切片的IHC染色，确定了特定的CD8+、CD4+、FoxP3+、CD20+和CD68+细胞亚群。同时进行了PD-L1和CD8/PD-L1双重染色。在肿瘤和肿瘤周围区域量化了细胞亚群密度。我们使用描述性统计来报告细胞亚群密度，并使用t检验比较按年龄、分级和BCR发生发展的组别。通过单变量和多变量逻辑回归分析BCR和转移性疾病的风险因素。结果：共纳入175名患者，中位年龄为63岁，中位术前PSA为8.2ng/ml。115名患者（66%）发生BCR，56名（32%）发生转移性疾病。CD68+细胞最为丰富（中位肿瘤内648.8/mm2，肿瘤周围247.6/mm2），而PD-L1+和PD-L1/CD8+细胞密度总体较低（PD-L1+中位肿瘤内162.4/mm2，肿瘤周围141.7/mm2；PD-L1/CD8+中位肿瘤内5.52/mm2，肿瘤周围3.41/mm2）。总体而言，分级组和T期与BCR和转移性疾病独立相关。肿瘤周围PD-L1+细胞密度较高是BCR的独立风险因素（OR 5.33，95%CI 1.31–21.61，p = 0.019）。尽管在高分级组3–5级肿瘤中观察到CD8+和CD4+细胞密度较高，但这些与BCR或转移的发生发展无相关性。结论：在我们的接受根治性前列腺切除术的前列腺癌患者队列中，高分级组和T期是BCR和转移的独立预测因素。尽管高分级组与CD8+细胞密度较高相关，但PD-L1+和PD-L1/CD8+细胞密度总体较低，这表明T细胞受体对肿瘤抗原的识别能力较低。进一步理解这一现象将影响未来前列腺癌免疫治疗策略的发展。