Abstract：
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.
摘要：
结直肠癌（CRC）在年龄小于50岁的个体（早发性CRC；EOCRC）中的发病率显著增加，然而，这种惊人的上升背后的病因和分子机制仍不清楚。我们比较了EOCRC和平均起病CRC（AOCRC）之间的肿瘤相关T细胞库，以揭示发病年龄的潜在独特的免疫微环境相关特征。我们的发现队列包括2000年至2020年在克利夫兰诊所接受手术切除的242例患者。EOCRC定义为诊断时年龄<50岁（N=126），AOCRC年龄≥60岁(N=116)。通过肿瘤的免疫测序测量T细胞受体(TCR)丰度和克隆性。Logistic回归模型用于评估TCR库特征与发病年龄之间的关联。适应性，种族,肿瘤位置,和舞台。在结直肠癌分子流行病学研究的152例EOCRC和1,984例AOCRC病例中重复了发现。与发现队列中的AOCRC肿瘤相比,EOCRC肿瘤具有显著更高的TCR多样性(赔率比(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这种关联(OR:0.74,95%CI:0.62-0.89,p=.0013)。在任一队列中,在EOCRC和AOCRC之间没有观察到TCR丰度的显著差异。更高的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研究T细胞多样性和适应性免疫应答在EOCRC的病因和结果中的作用。
