关键免疫T细胞群体在不同免疫原性潜能和免疫治疗反应可能性的恶性肿瘤中的差异浸润。

Differential Infiltration of Key Immune T-Cell Populations Across Malignancies Varying by Immunogenic Potential and the Likelihood of Response to Immunotherapy.

作者信息

Eljilany Islam, Coleman Sam, Tan Aik Choon, McCarter Martin D, Carpten John, Colman Howard, Naqash Abdul Rafeh, Puzanov Igor, Arnold Susanne M, Churchman Michelle L, Spakowicz Daniel, Salhia Bodour, Marin Julian, Ganesan Shridar, Ratan Aakrosh, Shriver Craig, Hwu Patrick, Dalton William S, Weiner George J, Conejo-Garcia Jose R, Rodriguez Paulo, Tarhini Ahmad A

机构信息

Departments of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Huntsman Cancer Institute, Salt Lake City, UT 84132, USA.

出版信息

Cells. 2024 Dec 3;13(23):1993. doi: 10.3390/cells13231993.

Abstract

Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate T-cell populations and their differential infiltration within different tumor types as estimated from mRNA co-expression levels of the corresponding cellular markers. We analyzed the mRNA co-expression levels of cellular biomarkers that define stem-like tumor-infiltrating lymphocytes (TILs), tissue-resident memory T-cells (TRM), early dysfunctional T-cells, late dysfunctional T-cells, activated-potentially anti-tumor (APA) T-cells and Butyrophilin 3A (BTN3A) isoforms, utilizing clinical and transcriptomic data from 1892 patients diagnosed with melanoma, bladder, ovarian, or pancreatic carcinomas. Real-world data were collected under the Total Cancer Care Protocol and the Avatar project (NCT03977402) across 18 cancer centers. Furthermore, we compared the survival outcomes following immune checkpoint inhibitors (ICIs) based on immune cell gene expression. In melanoma and bladder cancer, the estimated infiltration of APA T-cells differed significantly ( = 4.67 × 10 and = 5.80 × 10, respectively) compared to ovarian and pancreatic cancers. Ovarian cancer had lower TRM T-cell infiltration than melanoma, bladder, and pancreatic ( = 2.23 × 10, 3.86 × 10, and 7.85 × 10, respectively). Similar trends were noted with stem-like, early, and late dysfunctional T-cells. Melanoma and ovarian expressed BTN3A isoforms more than other malignancies. Higher densities of stem-like TILs; TRM, early and late dysfunctional T-cells; APA T-cells; and BTN3A isoforms were associated with increased survival in melanoma ( = 0.0075, 0.00059, 0.013, 0.005, 0.0016, and 0.041, respectively). The TRM gene signature was a moderate predictor of survival in the melanoma cohort (AUROC = 0.65), with similar findings in testing independent public datasets of ICI-treated patients with melanoma (AUROC 0.61-0.64). Key cellular elements related to immune activation are more heavily infiltrated within ICI-responsive versus non-responsive malignancies, supporting a central role in anti-tumor immunity. In melanoma patients treated with ICIs, higher densities of stem-like TILs, TRM T-cells, early dysfunctional T-cells, late dysfunctional T-cells, APA T-cells, and BTN3A isoforms were associated with improved survival.

摘要

实体瘤因肿瘤微环境(TME)的免疫原性潜力以及对免疫疗法的反应可能性而异。新兴文献已确定了关键免疫细胞群体,这些群体对TME内的免疫激活或抑制有显著影响。本研究调查了候选T细胞群体及其在不同肿瘤类型中的差异浸润情况,这些差异是根据相应细胞标志物的mRNA共表达水平估算得出的。我们利用来自1892例诊断为黑色素瘤、膀胱癌、卵巢癌或胰腺癌患者的临床和转录组数据,分析了定义干细胞样肿瘤浸润淋巴细胞(TILs)、组织驻留记忆T细胞(TRM)、早期功能失调T细胞、晚期功能失调T细胞、活化的潜在抗肿瘤(APA)T细胞和嗜乳脂蛋白3A(BTN3A)异构体的细胞生物标志物的mRNA共表达水平。在18个癌症中心,根据“全癌关爱协议”和“阿凡达项目”(NCT03977402)收集了真实世界数据。此外,我们根据免疫细胞基因表达比较了免疫检查点抑制剂(ICIs)治疗后的生存结果。在黑色素瘤和膀胱癌中,与卵巢癌和胰腺癌相比,APA T细胞的估计浸润显著不同(分别为4.67×10和5.80×10)。卵巢癌的TRM T细胞浸润低于黑色素瘤、膀胱癌和胰腺癌(分别为2.23×10、3.86×10和7.85×10)。在干细胞样、早期和晚期功能失调T细胞方面也观察到类似趋势。黑色素瘤和卵巢癌比其他恶性肿瘤更多地表达BTN3A异构体。在黑色素瘤中,较高密度的干细胞样TILs、TRM、早期和晚期功能失调T细胞、APA T细胞以及BTN3A异构体与生存率提高相关(分别为0.0075、0.00059、0.013、0.005、0.0016和0.041)。TRM基因特征是黑色素瘤队列中生存的中度预测指标(AUROC = 0.65),在测试接受ICI治疗的黑色素瘤患者的独立公共数据集时也有类似发现(AUROC为0.61 - 0.64)。与免疫激活相关的关键细胞成分在对ICI有反应的恶性肿瘤中比无反应的恶性肿瘤中浸润更严重,这支持了其在抗肿瘤免疫中的核心作用。在接受ICIs治疗的黑色素瘤患者中,较高密度的干细胞样TILs、TRM T细胞、早期功能失调T细胞、晚期功能失调T细胞、APA T细胞和BTN3A异构体与生存率提高相关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/979c/11640164/9564e00e45bc/cells-13-01993-g001a.jpg

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