Division of personalised oncology, Walter and Eliza Hall Institute, Melbourne, Australia.
Royal Melbourne Hospital, Melbourne, Australia.
PLoS One. 2024 Nov 27;19(11):e0301943. doi: 10.1371/journal.pone.0301943. eCollection 2024.
Immunotherapy 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.
Two 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.
A 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.
In 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.
免疫疗法在前列腺癌中的应用效果有限。这可能反映了肿瘤微环境（TME）的免疫抑制作用，先前的研究表明 PD-L1 表达水平低，免疫细胞浸润稀疏。我们旨在进一步描述原发性前列腺癌的免疫 TME，并将免疫亚群密度与临床结局相关联。
根据生化复发（BCR）的发生情况，确定了接受根治性前列腺切除术的两个不同患者队列，一个亚组具有高国际泌尿科病理学家协会（ISUP）分级组、复发性疾病，另一个亚组具有低级别、非复发性疾病。使用前列腺免疫组织化学（IHC）抗体鸡尾酒来区分肿瘤和肿瘤周围良性组织。使用连续切片的 IHC 染色来识别特定的 CD8+、CD4+、FoxP3+、CD20+ 和 CD68+细胞亚群。还进行了 PD-L1 和 CD8/PD-L1 双重染色。在肿瘤和肿瘤周围区域内量化细胞亚群密度。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 发展分组的结果。使用单变量和多变量逻辑回归分析 BCR 和转移性疾病发展的危险因素。
共纳入 175 例患者，中位年龄为 63 岁，中位术前 PSA 为 8.2ng/ml。115 例（66%）患者发生 BCR，56 例（32%）发生转移性疾病。CD68+细胞最为丰富（肿瘤内中位数为 648.8/mm2，肿瘤周围为 247.6/mm2），而 PD-L1+和 PD-L1/CD8+细胞密度总体较低（PD-L1+肿瘤内中位数为 162.4/mm2，肿瘤周围为 141.7/mm2；PD-L1/CD8+（肿瘤内中位数为 5.52/mm2，肿瘤周围为 3.41/mm2）。总体而言，分级组和 T 期是 BCR 和转移性疾病的独立相关因素。肿瘤周围 PD-L1+细胞密度较高是 BCR 的独立危险因素（OR 5.33，95%CI 1.31-21.61，p=0.019）。尽管在 3-5 级肿瘤中观察到更高的 CD8+和 CD4+细胞密度，但它们与 BCR 或转移的发生无关。
在我们接受根治性前列腺切除术的前列腺癌患者队列中，较高的分级组和 T 期是 BCR 和转移的独立预测因素。尽管分级组与较高的 CD8+细胞密度相关，但 PD-L1+和 PD-L1/CD8+细胞密度总体较低，表明肿瘤抗原的 T 细胞受体识别较低。进一步了解这种现象将影响前列腺癌未来免疫治疗策略的发展。
