借力推动前列腺癌 CAR-T 细胞治疗进展
Piggybacking toward Progress for CAR T-Cell Therapy in Prostate Cancer.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
外周血对 Toll 样受体 1/2 信号的 IFN 反应与接受 Sipuleucel-T 治疗的转移性前列腺癌男性患者更长的生存期相关
英文原题：Peripheral Blood IFN Responses to Toll-Like Receptor 1/2 Signaling Associate with Longer Survival in Men with Metastatic Prostate Cancer Treated with Sipuleucel-T.
查看英文原题
Peripheral Blood IFN Responses to Toll-Like Receptor 1/2 Signaling Associate with Longer Survival in Men with Metastatic Prostate Cancer Treated with Sipuleucel-T.
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中文摘要
越来越多的证据表明系统性固有免疫与肿瘤免疫监视相关。在晚期转移性去势抵抗性前列腺癌中，黑人患者被发现炎症标志物水平更高，且在接受 sipuleucel-T（sip-T）治疗——一种经 FDA 批准的自体细胞疗法——后生存期更长。我们假设这些差异可能源于此前报道的模式识别受体信号通路的种族差异，该通路广泛调控固有炎症，从而控制适应性免疫细胞的活化、趋化和功能。我们发现，外周血单个核细胞对 Toll 样受体 1/2（TLR1/2）——一种细菌和肠道微生物组成分的传感器——的 IFN-β 应答，与两个独立 mCRPC 男性队列中 sip-T 治疗后显著更长的生存期相关（发现队列：n = 106，HR = 0.12；P = 0.019；验证队列：n = 28，HR < 0.01；P = 0.047）。TLR1/2 刺激后更高的 IFN-β 诱导水平，与 mCRPC 中疫苗效力生物标志物及其他预后因素相比，具有更低的 HR。TLR1/2 依赖的细胞因子诱导在黑人个体中更强（IFN-β 高 1.2 倍；P = 0.04），但其与生存期的关联独立于种族或疫苗诱导的肿瘤抗原特异性 T 细胞数量。对 TLR1/2 信号的 IFN-β 应答与广泛的、不依赖肿瘤抗原的刺激后产生 IFN-γ 的 T 细胞数量增加相关。因此，外周固有免疫存在种族差异，可能预测 sip-T 治疗后的生存期，并与 mCRPC 患者的外周 T 细胞功能相关。意义：迫切需要确定决定癌症免疫治疗成功的因素，尤其是在mCRPC等难治性肿瘤类型中：既是为了识别可能从此类疗法中获益的患者，也是为了揭示使癌症患者对免疫治疗敏感的途径。我们的工作将外周功能性免疫反应与mCRPC男性接受细胞免疫治疗后的种族和生存联系起来。
展开英文摘要原文
UNLABELLED: Mounting evidence links systemic innate immunity with cancer immune surveillance. In advanced metastatic castration-resistant prostate cancer (mCRPC), Black patients have been found to have increased inflammatory markers and longer survival after sipuleucel-T (sip-T) therapy, an FDA-approved, autologous cell therapy.
We hypothesized these differences may be explained by previously reported ancestral differences in pattern recognition receptor signaling, which broadly governs innate inflammation to control adaptive immune cell activation, chemotaxis, and functionality.
We discovered that peripheral blood mononuclear cell IFN-β responses to Toll-like receptor 1/2 (TLR1/2), a sensor of bacterial and gut microbiome constituents, associated with significantly longer survival after sip-T therapy in two separate cohorts of men with mCRPC (discovery cohort: n = 106, HR = 0. 12; P = 0. 019; validation cohort: n = 28, HR < 0. 01; P = 0. 047). Higher IFN-β induction after TLR1/2 stimulation was associated with lower HRs than biomarkers of vaccine potency and other prognostic factors in mCRPC.
TLR1/2-dependent cytokine induction was stronger in Black individuals (1. 2-fold higher for IFN-β; P = 0. 04) but was associated with survival independently of race or numbers of vaccine-induced tumor antigen-specific T cells. IFN-β responses to TLR1/2 signaling correlated with increased numbers of IFN-γ producing T cells after broad, tumor antigen-independent stimulation.
Thus, peripheral innate immunity differs by race, may predict survival after sip-T, and associates with peripheral T-cell functionality in men with mCRPC. SIGNIFICANCE: The identification of factors that determine successful cancer immunotherapy, particularly in refractory tumor types like mCRPC, is urgently needed: both to identify patients that may benefit from such therapies and to uncover routes to sensitize patients with cancer to immunotherapy.
Our work links functional peripheral immune responses with race and survival after cellular immunotherapy in men with mCRPC.
论文信息
- 作者
- Brown MC、D'Anniballe VM、Boczkowski D、Kandadi H、Sheikh N、Kornahrens W Jr、Heath EI、Thakur A
- 单位
- Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Cancer research communications2024 Oct 1
- 原文标识
- PubMed 39320053 · DOI 10.1158/2767-9764.CRC-24-0439
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