γδT cells play a pivotal role in cancer immune surveillance, yet the current knowledge of their function across the compartments in solid tumors is meager. To address this gap, we developed a comprehensive γδT-omics platform that integrates functional screening, biomimetic migration assays, γδTCR repertoire analysis, and transcriptomic profiling. Using matched samples from 31 patients with microsatellite-stable colorectal cancer (CRC), we analyzed γδT cells from peripheral blood (PBLsγδ), adjacent colon (LPLsγδ), primary tumors (pTILsγδ), and liver metastases (mTILsγδ). This approach uncovered striking compartmentalization of γδT cell phenotypes, clonality, and function. Tumor-reactive, clonally expanded Vδ1⁺ γδT cells were enriched in primary tumors and shared transcriptional and functional features with lamina propria lymphocytes (LPLs). In contrast, Vδ1⁺ γδT cells from liver metastases lacked tumor reactivity, exhibited distinct γδTCR repertoires, and expressed transcriptional signatures associated with TGF-β-mediated suppression and cellular quiescence, suggesting they are shaped by tissue-specific environmental cues. CXCL16 secretion by tumor cells initiated Vδ1⁺ LPLsγδ migration, which was further amplified by γδTCR-mediated CCL5 induction from pTILsγδ, leading to CCR5 downregulation and subsequent entrapment of pTILsγδ within the tumor microenvironment. Accordingly, our clinical data from an independent second cohort of 69 patients showed that infiltration by pTILsγδ, but not mTILsγδ, is associated with a protective effect against CRC progression. In summary, our study offers a compartment-resolved perspective on γδT cell behavior in CRC, revealing key trafficking and functional mechanisms, and enabling the identification of novel tumor-reactive γδTCRs and migratory cues to inform immunotherapeutic strategies for both primary and metastatic CRC.
Gatti et al. (Sat,) studied this question.