Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Biomedical and Health Informatics, School of Health Professions, Rutgers, The State University of New Jersey, Newark, NJ, USA.
Prostate Cancer Prostatic Dis. 2023 Mar;26(1):105-112. doi: 10.1038/s41391-022-00547-0. Epub 2022 May 14.
Data on advanced prostate cancer (PCa) suggest more prior systemic therapies might reduce tumor immune responsiveness. In treatment-naïve primary PCa, recent work correlated intratumoral plasma cell content with enhanced tumor immune-responsiveness. We sought to identify features of localized PCa at a high risk of recurrence following local treatment with high plasma cell content to help focus future immune-based neoadjuvant trials.
We performed retrospective analyses of molecular profiles from three independent cohorts of over 1300 prostate tumors. We used Wilcoxon Rank Sum to compare molecular pathways between tumors with high and low intratumoral plasma cell content and multivariable Cox proportional hazards regression analyses to assess metastasis-free survival.
We validated an expression-based signature for intratumoral plasma cell content in 113 primary prostate tumors with both RNA-expression data and digital image quantification of CD138+ cells (plasma cell marker) based on immunohistochemisty. The signature showed castration-resistant tumors (n = 101) with more prior systemic therapies contained lower plasma cell content. In high-grade primary PCa, tumors with high plasma cell content were associated with increased predicted response to immunotherapy and decreased response to androgen-deprivation therapy. Master regulator analyses identified upregulated transcription factors implicated in immune (e.g. SKAP1, IL-16, and HCLS1), and B-cell activity (e.g. VAV1, SP140, and FLI-1) in plasma cell-high tumors. Master regulators overactivated in tumors with low plasma cell content were associated with shorter metastasis-free survival following radical prostatectomy.
Markers of plasma cell activity might be leveraged to augment clinical trial targeting and selection and better understand the potential for immune-based treatments in patients with PCa at a high risk of recurrence following local treatment.
关于晚期前列腺癌（PCa）的数据表明，更多的先前系统性治疗可能会降低肿瘤的免疫反应性。在初治原发性 PCa 中，最近的研究表明肿瘤内浆细胞含量与增强的肿瘤免疫反应性相关。我们试图确定局部治疗后具有高复发风险的局限性 PCa 的特征，这些特征具有高浆细胞含量，有助于集中未来基于免疫的新辅助试验。
我们对三个独立队列的超过 1300 个前列腺肿瘤的分子谱进行了回顾性分析。我们使用 Wilcoxon 秩和检验比较了肿瘤内浆细胞含量高和低的肿瘤之间的分子途径，并使用多变量 Cox 比例风险回归分析评估无转移生存。
我们在 113 个原发性前列腺肿瘤中验证了基于 RNA 表达数据和基于免疫组化的 CD138+细胞（浆细胞标志物）数字图像量化的肿瘤内浆细胞含量的表达谱为基础的签名。该签名显示具有更多先前系统性治疗的去势抵抗性肿瘤（n=101）含有较低的浆细胞含量。在高级别原发性 PCa 中，高浆细胞含量的肿瘤与增加的预测免疫治疗反应和降低的雄激素剥夺治疗反应相关。主调控因子分析确定了上调的转录因子，这些转录因子与免疫（例如 SKAP1、IL-16 和 HCLS1）和 B 细胞活性（例如 VAV1、SP140 和 FLI-1）相关。在浆细胞含量低的肿瘤中过度激活的主调控因子与根治性前列腺切除术后无转移生存时间较短相关。
浆细胞活性标志物可用于增强临床试验靶向和选择，并更好地理解局部治疗后具有高复发风险的 PCa 患者免疫治疗的潜力。
