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. 2024 Oct 1;116(10):1645-1653.
doi: 10.1093/jnci/djae143.

Differences in tumor-associated T-cell receptor repertoires between early-onset and average-onset colorectal cancer

Ya-Yu Tsai  1 , Kanika G Nair  2   3 , Shimoli V Barot  3 , Shao Xiang  4 , Suneel Kamath  2   3   5   6 , Marilena Melas  7 , Christopher P Walker  8 , Raghvendra M Srivastava  9 , Nicole Osborne  9 , Timothy A Chan  9 , Jonathan B Mitchem  4   10   11 , Joseph D Bonner  8 , Kevin J McDonnell  8 , Gregory E Idos  8 , Rebeca Sanz-Pamplona  12   13   14   15 , Joel K Greenson  16 , Hedy S Rennert  17 , Gad Rennert  17 , Victor Moreno  12   13   14   18 , Stephen B Gruber  8 , Alok A Khorana  2   3   6 , David Liska  2   10   19 , Stephanie L Schmit  1   2   20
Affiliations

Differences in tumor-associated T-cell receptor repertoires between early-onset and average-onset colorectal cancer

Ya-Yu Tsai et al. J Natl Cancer Inst. .

Abstract

The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early-onset CRC [EOCRC]) has substantially increased, and 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 younger than age 50 years at diagnosis (N = 126) and AOCRC as 60 years of age or older (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 1984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study. EOCRC tumors had significantly higher TCR diversity compared with AOCRC tumors in the discovery cohort (odds ratio [OR] = 0.44, 95% confidence interval [CI] = 0.32 to 0.61, P < .0001). This association was also observed in the replication cohort (OR = 0.74, 95% CI = 0.62 to 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.

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Conflict of interest statement

GEI: receives/received research funding from Myriad Genetics and Laboratories. JKG: consultant for Guardant Health. VM: owns stock in Aniling. SBG: co-founder of Brogent International LLC with equity. SK: consulting and advisory role in Exelixis, Tempus, Guardant Health, and SeaGen. AAK: consulting honoraria from Janssen, Bayer, BMS, Sanofi, Pfizer, and Anthos. DL: consulting and advisory roles in Olympus Medical Systems and research funding from Merck. Others: none.

Figures

Figure 1.
Figure 1.
Conceptual framework for the relationship between T-cell repertoire and colorectal cancer age of onset.
Figure 2.
Figure 2.
Associations between age of onset (EOCRC vs AOCRC; AOCRC as reference) and TCR features. A) TCR abundance in CCF Discovery Cohort. B) TCR clonality in CCF Discovery Cohort. C) TCR abundance in MECC Replication Cohort. D) TCR clonality in MECC Replication Cohort.
Figure 3.
Figure 3.
Correlation of T-cell receptor (TCR) clonality and age of colorectal cancer onset in normal colon and tumor tissues from the Colonomics study. A) Correlation between age and clonality in tumor tissues. B) Correlation between age and clonality in normal colon tissues.
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