免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
单细胞分析揭示黑色素瘤中与检查点治疗应答相关的功能异质性耗竭 CD8+ T 细胞亚群
英文原题：Single-Cell Analyses Reveal a Functionally Heterogeneous Exhausted CD8+ T-cell Subpopulation That Is Correlated with Response to Checkpoint Therapy in Melanoma.
查看英文原题
Single-Cell Analyses Reveal a Functionally Heterogeneous Exhausted CD8+ T-cell Subpopulation That Is Correlated with Response to Checkpoint Therapy in Melanoma.
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中文摘要
PD-1 通路抑制剂已经彻底改变了癌症治疗。然而，大多数患者并不能持久获益，这凸显了需要生物标志物来将患者分层为缓解者或非缓解者。尽管 CD8+ TIL（肿瘤浸润淋巴细胞）与免疫检查点治疗缓解相关，但对于哪些 CD8+ TIL 亚群具有最大预后价值尚无共识。临床前研究聚焦于祖细胞样耗竭 CD8+ T 细胞（TPEX），因为在响应 PD-1 抑制剂时，TPEX 比其他耗竭 T 细胞（TEX）亚群增殖更多。然而，免疫检查点抑制剂治疗会驱动 TPEX 分化为其他可介导抗肿瘤免疫的 TEX 群体。这些数据使识别患者中可预测免疫检查点抑制剂治疗缓解的、具有预后重要性的 T 细胞群体变得复杂。在本研究中，我们发现，晚期黑色素瘤患者若 20% 的 CD8+ TIL 共表达 PD-1 和 CTLA4（称为 CPHi TIL），则接受 PD-1 单药治疗后客观缓解率和生存优于低于该阈值的患者。利用 bulk 和单细胞 RNA 测序对 CPHi TIL 亚群进行表征显示，尽管 TPEX 样细胞存在于 CPHi 亚群中，但它们在上述细胞中占少数。相反，CPHi 群体在数量上由其他亚群主导，包括增殖中、终末耗竭样、细胞毒性样和/或驻留记忆样 TEX 群体，以及一个富含糖酵解基因的亚群。总体而言，这些数据表明 CPHi TIL 与黑色素瘤中的缓解相关，但该 TIL 亚群是不同亚群的异质性混合体，可能在检查点阻断后对抗肿瘤免疫有差异性贡献。意义：与免疫治疗应答相关的 PD-1+ CTLA4+ CD8+ TIL（肿瘤浸润淋巴细胞）群体是多个亚群的异质性混合体，这对优化基于检查点的免疫治疗具有重要意义。
展开英文摘要原文
PD-1 pathway inhibitors have revolutionized cancer therapy.
However, most patients do not durably benefit, highlighting the need for biomarkers to stratify patients as responders or nonresponders. Although CD8+ tumor-infiltrating lymphocytes (TIL) have been associated with immune checkpoint therapy response, there is no consensus on which CD8+ TIL subpopulations have the most prognostic value. Preclinical studies have focused on progenitor-like exhausted CD8+ T cells (TPEX) because TPEX proliferate more in response to PD-1 inhibitors than other exhausted T-cell (TEX) subpopulations.
However, immune checkpoint inhibitor treatment drives TPEX differentiation into other TEX populations that can mediate antitumor immunity. These data complicate the ability to identify prognostically important T-cell populations in patients that predict immune checkpoint inhibitor treatment response. In this study, we found that patients with advanced melanoma with 20% of CD8+ TILs coexpressing PD-1 and CTLA4 (termed CPHi TIL) had better objective response rates and survival following PD-1 monotherapy than those below this threshold. Characterization of the CPHi TIL subset using bulk and single-cell RNA sequencing showed that although TPEX-like cells were present within the CPHi subset, they were in the minority of these cells.
Rather, the CPHi population was numerically dominated by other subsets, including cycling, terminally exhausted-like, cytotoxic-like, and/or resident memory-like TEX populations, and a subset enriched for glycolytic genes. Collectively, these data show that CPHi TILs correlate with response in melanoma, but this TIL subset is a heterogeneous mix of different subpopulations that may differentially contribute to antitumor immunity following checkpoint blockade.
Significance: The PD-1+ CTLA4+ CD8+ tumor-infiltrating lymphocyte population correlating with immunotherapy response is a heterogeneous mix of subpopulations, which has important implications for optimizing checkpoint-based immunotherapy.
论文信息
- 作者
- Mahuron KM、Shahid O、Sao P、Wu C、Haugh AM、Huppert LA、Levine LS、Lowe MM
- 第一作者单位
- Department of Surgery, University of California, San Francisco, San Francisco, California.United States
- 通讯作者单位
- Department of Medicine, University of California, San Francisco, San Francisco, California.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 research2025 Apr 15
- 原文标识
- PubMed 40042995 · DOI 10.1158/0008-5472.CAN-23-3918
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