Tilsed Caitlin M, Brotman Joshua, O'Brien Shaun, Lee Brennan, Moon Edmund, Albelda Steven M
Pulmonary, Critical Care, and Allergy Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
Informatics and Predictive Sciences, Mechanisms of Cancer Resistance, Bristol Myers Squibb, Cambridge, MA, United States.
Immunohorizons. 2025 Apr 26;9(6). doi: 10.1093/immhor/vlaf013.
Tissue resident memory T cells (TRM) play a critical role in cancer immunity and their presence in solid tumors is associated with improved prognosis and response to therapy. Although TRM have been identified and their function characterized in lung cancers, little is known regarding TRM outside of a tissue context, such as within malignant pleural effusions (MPE). As MPE are routinely drained and collected to manage symptoms, analysis of this fluid can provide an insight into the peri-tumoral environment. In this study, we performed flow cytometry and single cell RNAseq (scRNAseq) on MPE associated with non-small lung cancer and examined the phenotype and function of TRM. We found that 14% of CD8+ T cells and 6% of CD4+ T cells were TRM, as defined by the phenotype of CD45RO+CCR7-CD62L- and expressing 1 or both of CD69 and CD103. The scRNAseq revealed distinct clusters expressing TRM-associated genes including ITGAE and CD49A and lacking expression of SELL, CCR7, and IL7RA. TRM did not differ from other memory T cell subsets, such as T central memory (TCM) and T effector memory (TEM) cells, in expression of the inhibitory markers PD-1, TIGIT, and CD39. When TRM function was assessed by measuring the production of IFN-γ, TNF-α, and CD107a after stimulation with αnti-CD3 antibodies in vitro, TRM had comparable function to T effector cells (TE), indicating that despite expression of exhaustion markers these cells retained effector function. Finally, we found that CD69 expression, and not CD103 expression, on TRM was associated with production of effector cytokines.
组织驻留记忆T细胞（TRM）在癌症免疫中发挥着关键作用，它们在实体瘤中的存在与预后改善及对治疗的反应相关。尽管已在肺癌中鉴定出TRM并对其功能进行了表征，但对于组织外环境中的TRM，如恶性胸腔积液（MPE）中的TRM，我们了解甚少。由于MPE通常会被引流和收集以控制症状，对这种液体的分析可以深入了解肿瘤周围环境。在本研究中，我们对与非小细胞肺癌相关的MPE进行了流式细胞术和单细胞RNA测序（scRNAseq），并检测了TRM的表型和功能。我们发现，按照CD45RO+CCR7-CD62L-的表型定义，并表达CD69和CD103中的1个或2个，14%的CD8+T细胞和6%的CD4+T细胞为TRM。scRNAseq显示出表达TRM相关基因（包括ITGAE和CD49A）且缺乏SELL、CCR7和IL7RA表达的不同细胞簇。TRM在抑制性标志物PD-1、TIGIT和CD39的表达上与其他记忆T细胞亚群，如中央记忆T细胞（TCM）和效应记忆T细胞（TEM）没有差异。当通过在体外使用抗CD3抗体刺激后测量IFN-γ、TNF-α和CD107a的产生来评估TRM功能时，TRM与效应T细胞（TE）具有相当的功能，这表明尽管表达了耗竭标志物，但这些细胞仍保留了效应功能。最后，我们发现TRM上的CD69表达而非CD103表达与效应细胞因子的产生相关。
