Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses

Authors

Saad, M., Thoms, A., Yin, Y. S., Mamede, I., Rahman, A., Chen, R., Carrasco, S. E., Darcy, P. W., Goto, N., Tavazoie, S. F., Bilate, A. M., Mucida, D.

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer mortality, with most cases refractory to immunotherapy. Distinguishing tumor-induced from steady-state mucosal T cell responses has been a critical barrier to understanding antitumor immunity in CRC. Using orthotopic transplantation of CRC organoids with and without metastatic potential, combined with temporal T cell fate-mapping, we show that non-metastatic tumors elicit early recruitment of CD8{beta}+ and CD4+ T cells that acquired cytotoxic and Th1-like programs, whereas pro-metastatic tumors induce a naive-like, hypoactivated state. Tumor-infiltrating CD4+ T cells underwent clonal expansion, including clones recognizing microbial and dietary antigens. T cells in physical contact with tumor cells, identified by uLIPSTIC, were enriched for expanded and cytotoxic clones. Fate-mapped T cells from non-metastatic tumors suppressed tumor growth in an IFN-{gamma}-dependent manner, whereas pro-metastatic tumor-derived T cells failed to do so. Mechanistically, pro-metastatic tumors downregulated MHCII, and Ciita targeting in non-metastatic organoids reduced CD4+ clonal expansion and led to tumor progression. Together, these findings define divergent early T cell trajectories associated with CRC metastatic potential, indicating that ineffective local immune engagement precedes metastatic dissemination.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Jul 2026.

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