| First Author | Uzhachenko RV | Year | 2025 |
| Journal | Front Immunol | Volume | 16 |
| Pages | 1593913 | PubMed ID | 41058706 |
| Mgi Jnum | J:373121 | Mgi Id | MGI:8252713 |
| Doi | 10.3389/fimmu.2025.1593913 | Citation | Uzhachenko RV, et al. (2025) CD8(+) T-NK cell crosstalk establishes preemptive immunosurveillance to eliminate antigen-escape tumors. Front Immunol 16:1593913 |
| abstractText | BACKGROUND AND OBJECTIVE: Tumor antigen-escape variants undermine immunotherapy by subverting lymphocyte effector functions and reshaping tumor-immune dynamics. It is essential to delineate functional interplay within immune networks during tumor progression. We investigated whether homeostatic crosstalk between CD8(+)T cells and natural killer (NK) cells preempts tumor antigen-escape. METHODS: Adoptive CD8(+)T cell transfers were administered before (D(-7), homeostatic pre-priming) or after (D(+1)) tumor establishment in Rag1(-/-) and Rag1(-/-)gammac(-/-) mice. Antigen presentation, immune activation, proliferation, cytotoxicity, and memory were quantified by flow cytometry, live bioluminescence and confocal imaging. Monoculture, co-culture, and a 3D silica nanofiber carpet mimicking basement-membrane-like topography modeled intercellular interactions. Signaling arrays and motion metrics (Speed-Distance Index, deceleration) were conducted. Human ligand-receptor pairs engaged in CD8(+)T-NK crosstalk were probed in silico. RESULTS AND DISCUSSION: Pre-tumor D(-7) CD8(+)T cell transfer completely suppressed antigen-escape tumors with NK cells as major effectors showing elevated CD25, CD69, CD107a, and GzmB, marking activated and effector phenotype, and promoting central-memory CD62L(+)CD44(+)CD8(+)T(CM) precursors. By contrast, post-tumor D(+1)-transferred CD8(+)T cells allowed emergence of tumor variants resistant to antigen-specific cytolysis as assessed on day 25, despite those T cells retaining higher intrinsic cytotoxic capacity than the D(-7) T cell cohort. Mechanistically, CD8(+)T and NK cells formed stable contacts through pseudopodial intercellular nanotubes enabling bidirectional membrane exchange and signaling via STAT, Akt, and mTOR pathways, augmenting NK effector function and promoting CD8(+)T(CM) differentiation. In silico analysis identified human ligand-receptor pairs engaged in CD8(+)T-NK adhesion, stimulatory and regulatory axes, including CD200-CD200R, PD-L1-PD-1, and CD18/CD11a-DNAM-1 (CD226). Together, data support a three-phase model of preemptive immunosurveillance initiated by early CD8(+)T-NK crosstalk. CONCLUSION: Homeostatic conditioning and effector cooperativity between CD8(+)T and NK cells protect against tumor immune escape. The findings uncover a mechanistic axis of preemptive immunosurveillance that lays the foundation for next-generation preventive immunotherapies to control antigen-escape tumors. |
