Lee Ji-Ae, Park Hye Eun, Lee Dae-Won, Han Sae-Won, Kim Tae-You, Jeong Seung-Yong, Park Kyu Joo, Bae Jeong Mo, Kang Gyeong Hoon
Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-Do, Republic of Korea.
Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Front Immunol. 2025 May 30;16:1601188. doi: 10.3389/fimmu.2025.1601188. eCollection 2025.
T-cell exhaustion is a major mechanism of immune evasion. Recently, the therapeutic and prognostic implications of progenitor exhausted T cells (Tpex) and terminally exhausted T cells (Ttex) have been explored in various cancer types. This study explored the immunogenomic characteristics and prognostic implications of Tpex and Ttex in colorectal cancers (CRCs).
We performed multiplex immunofluorescence (mIF) using antibodies against CK, CD3, CD8, TCF1, and FOXP3 to assess diverse subsets of tumor-infiltrating lymphocytes (TILs) in 517 patients with stage III or high-risk stage II CRCs. We compared the infiltration level of these TIL subsets with the genetic profiles of CRCs, including microsatellite instability (MSI), tumor mutational burden (TMB), and mutations in 40 tumor-associated genes across five biological pathways.
CD8 T cell density, the CD8/CD3 ratio, and the Ttex/CD8 T cell ratio were elevated in microsatellite instability-high and tumor mutational burden-high tumors. Survival analysis showed that, higher CD8 T cell density, higher regulatory T cell/CD3 T cell ratio, and higher Ttex/CD8 T cell ratio exhibited better 5-year relapse-free survival (RFS) rates. When tumors were categorized into CD8-high, CD8-low/Ttex-low, and CD8-low/Ttex-high groups, the CD8-high and CD8-low/Ttex-high groups showed better 5-year RFS than the CD8-low/Ttex-low group.
Ttex infiltration is associated with MSI and TMB status and may serve as a prognostic marker of CRCs.
T细胞耗竭是免疫逃逸的主要机制。最近，已在多种癌症类型中探索了祖细胞耗竭性T细胞（Tpex）和终末耗竭性T细胞（Ttex）的治疗和预后意义。本研究探讨了Tpex和Ttex在结直肠癌（CRC）中的免疫基因组特征和预后意义。
我们使用抗CK、CD3、CD8、TCF1和FOXP3的抗体进行多重免疫荧光（mIF），以评估517例III期或高危II期CRC患者肿瘤浸润淋巴细胞（TIL）的不同亚群。我们将这些TIL亚群的浸润水平与CRC的基因谱进行了比较，包括微卫星不稳定性（MSI）、肿瘤突变负担（TMB）以及五个生物学途径中40个肿瘤相关基因的突变情况。
在微卫星不稳定性高和肿瘤突变负担高的肿瘤中，CD8 T细胞密度、CD8/CD3比值和Ttex/CD8 T细胞比值升高。生存分析表明，较高的CD8 T细胞密度、较高的调节性T细胞/CD3 T细胞比值和较高的Ttex/CD8 T细胞比值表现出更好的5年无复发生存率（RFS）。当肿瘤分为CD8高、CD8低/Ttex低和CD8低/Ttex高组时，CD8高组和CD8低/Ttex高组的5年RFS优于CD8低/Ttex低组。
Ttex浸润与MSI和TMB状态相关，可能作为CRC的预后标志物。
