Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer,Cancer Discovery

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Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer
Cancer Discovery ( IF 29.7 ) Pub Date : 2022-07-18 , DOI: 10.1158/2159-8290.cd-21-1248
Aislyn Schalck _{1,

2} , Donastas Sakellariou-Thompson _{3,

4} , Marie-Andrée Forget _{3,

4} , Emi Sei ₁ , Tara G Hughes ₁ , Alexandre Reuben ₅ , Shanshan Bai ₁ , Min Hu ₁ , Tapsi Kumar _{1,

2} , Mark W Hurd ₆ , Matthew H G Katz ₇ , Ching-Wei D Tzeng ₇ , Shubham Pant ₈ , Milind Javle ₈ , David R Fogelman ₈ , Anirban Maitra _{2,

6,

9} , Cara L Haymaker ₁₀ , Michael P Kim ₇ , Nicholas E Navin _{1,

2,

11} , Chantale Bernatchez _{3,

4}

Affiliation

Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas.
Department of Biologics Development, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distributions of TIL populations. The CD8+ TIL contained a putative transitional GZMK+ population based on T-cell receptor clonotype sharing, and cell-state trajectory analysis showed similarity to a GZMB+PRF1+ cytotoxic and a CXCL13+ dysfunctional population. Statistical analysis suggested that certain TIL states, such as dysfunctional and inhibitory populations, often occurred together. Finally, analysis of cultured TIL revealed that high-frequency clones from effector populations were preferentially expanded. These data provide a framework for understanding the PDAC TIL landscape for future TIL use in immunotherapy for PDAC. Significance: To improve the efficacy of immunotherapy in PDAC, there is a great need to understand the PDAC TIL landscape. This study represents a reference of PDAC TIL subpopulations and their relationships and provides a foundation upon which to base future immunotherapeutic efforts. This article is highlighted in the In This Issue feature, p. 2221

中文翻译：

单细胞测序揭示胰腺癌肿瘤浸润淋巴细胞状态的轨迹

胰腺导管腺癌（PDAC）的有效治疗方法很少。由于缺乏对 PDAC 中肿瘤浸润淋巴细胞 (TIL) 状况的了解，免疫疗法是一种有吸引力的替代策略，但仍然具有挑战性。为了生成 T 细胞亚群的参考，我们使用单细胞转录组和 T 细胞受体分析对来自 57 个 PDAC 样本、22 个未受影响/正常样本和培养 TIL 的 80,000 个 T 细胞进行了分析。这些数据揭示了 TIL 群体的 20 种细胞状态和异质分布。 CD8+ TIL 包含基于 T 细胞受体克隆型共享的推定过渡 GZMK+ 群体，细胞状态轨迹分析显示与 GZMB+PRF1+ 细胞毒性群体和 CXCL13+ 功能障碍群体相似。统计分析表明，某些 TIL 状态（例如功能失调和抑制群体）经常同时发生。最后，对培养的 TIL 的分析表明，来自效应群体的高频克隆优先扩增。这些数据为了解 PDAC TIL 前景提供了一个框架，以便未来 TIL 在 PDAC 免疫治疗中的使用。意义：为了提高 PDAC 免疫治疗的疗效，非常需要了解 PDAC TIL 情况。这项研究代表了 PDAC TIL 亚群及其关系的参考，并为未来的免疫治疗工作奠定了基础。本文在本期专题第 12 页中重点介绍。 2221

更新日期：2022-07-18

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