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Updated: Oct 11, 2025
Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
Tumor evolution selectively inactivates the core microRNA machinery for immune evasion
Tian-Yu Song1,2,3, Min Long1,3, Hai-Xin Zhao4
1Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Abstract:
Cancer cells acquire genetic heterogeneity to escape from immune surveillance during tumor evolution, but a systematic approach to distinguish driver from passenger mutations is lacking. Here we investigate the impact of different immune pressure on tumor clonal dynamics and immune evasion mechanism, by combining massive parallel sequencing of immune edited tumors and CRISPR library screens in syngeneic mouse tumor model and co-culture system. We find that the core microRNA (miRNA) biogenesis and targeting machinery maintains the sensitivity of cancer cells to PD-1-independent T cell-mediated cytotoxicity. Genetic inactivation of the machinery or re-introduction of ANKRD52 frequent patient mutations dampens the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells, largely by abolishing miR-155-targeted silencing of suppressor of cytokine signaling 1 (SOCS1). Expression of each miRNA machinery component strongly correlates with intratumoral T cell infiltration in nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway can be exploited by cancer cells to escape from T cell-mediated elimination and immunotherapy.
Insights
Cancer cells use microRNA (miRNA) machinery to evade T cell attacks, a key immune evasion mechanism. Disrupting this pathway could improve cancer immunotherapy effectiveness.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Cancer cells develop genetic diversity to evade immune surveillance.
- A systematic method to differentiate driver from passenger mutations is needed.
- Immune pressure influences tumor evolution and immune evasion.
Purpose of the Study:
- To investigate how immune pressure affects tumor clonal dynamics.
- To identify immune evasion mechanisms in cancer cells.
- To understand the role of microRNA (miRNA) biogenesis in immune sensitivity.
Main Methods:
- Massive parallel sequencing of immune-edited tumors.
- CRISPR library screens in syngeneic mouse models.
- Co-culture systems to study cancer cell-immune cell interactions.
Main Results:
- The core miRNA biogenesis and targeting machinery is crucial for T cell-mediated cytotoxicity.
- Inactivating miRNA machinery or introducing ANKRD52 mutations reduces JAK-STAT-interferon-γ signaling and antigen presentation.
- This occurs by inhibiting miR-155 silencing of SOCS1, impacting immune response.
- miRNA machinery component expression correlates with T cell infiltration in human cancers.
Conclusions:
- The conserved miRNA pathway is exploited by cancer cells for immune escape.
- Targeting miRNA machinery may enhance T cell-mediated elimination and immunotherapy outcomes.
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