The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early onset CRC; EOCRC) has substantially increased, yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. We compared tumor-associated T cell repertoires between EOCRC and average-onset CRC (AOCRC) to uncover potentially unique immune microenvironment-related features by age of onset. Our discovery cohort included 242 patients who underwent surgical resection at Cleveland Clinic from 2000 to 2020. EOCRC was defined as age < 50 years at diagnosis (N = 126), and AOCRC as age ≥ 60 years (N = 116). T cell receptor (TCR) abundance and clonality were measured by immunosequencing of tumors. Logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 EOCRC and 1,984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study. EOCRC tumors had significantly higher TCR diversity compared to AOCRC tumors in the discovery cohort (Odds Ratio (OR):0.44, 95% Confidence Interval (CI):0.32-0.61, p < .0001). This association was also observed in the replication cohort (OR : 0.74, 95% CI : 0.62-0.89, p = .0013). No significant differences in TCR abundance were observed between EOCRC and AOCRC in either cohort. Higher TCR diversity, suggesting a more diverse intratumoral T cell response, is more frequently observed in EOCRC than AOCRC. Further studies are warranted to investigate the role of T cell diversity and the adaptive immune response more broadly in the etiology and outcomes of EOCRC.

中文翻译：

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早发性结直肠癌和平均发病性结直肠癌肿瘤相关 T 细胞受体库的差异


50 岁以下人群中结直肠癌 (CRC) 的发病率（早发 CRC；EOCRC）大幅增加，但这种惊人上升背后的病因和分子机制仍不清楚。我们比较了 EOCRC 和平均发病 CRC (AOCRC) 之间的肿瘤相关 T 细胞库，以发现按发病年龄划分的潜在独特的免疫微环境相关特征。我们的发现队列包括 242 名 2000 年至 2020 年在克利夫兰诊所接受手术切除的患者。EOCRC 定义为诊断时年龄 < 50 岁 (N = 126)，AOCRC 定义为年龄 ≥ 60 岁 (N = 116)。通过肿瘤免疫测序测量 T 细胞受体 (TCR) 丰度和克隆性。使用 Logistic 回归模型评估 TCR 谱特征与发病年龄之间的关联，并根据性别、种族、肿瘤位置和分期进行调整。研究结果在结直肠癌分子流行病学研究的 152 例 EOCRC 和 1,984 例 AOCRC 病例中得到重复。在发现队列中，与 AOCRC 肿瘤相比，EOCRC 肿瘤具有显着更高的 TCR 多样性（比值比 (OR)：0.44，95% 置信区间 (CI)：0.32-0.61，p < .0001）。在复制队列中也观察到了这种关联（OR：0.74，95% CI：0.62-0.89，p = 0.0013）。在任一队列中，EOCRC 和 AOCRC 之间的 TCR 丰度均未观察到显着差异。较高的 TCR 多样性表明肿瘤内 T 细胞反应更加多样化，在 EOCRC 中比 AOCRC 中更常见。需要进一步的研究来更广泛地调查 T 细胞多样性和适应性免疫反应在 EOCRC 病因和结果中的作用。