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Updated: Feb 16, 2026
Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing
Deng Pan1, Aya Kobayashi1,2, Peng Jiang3
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Abstract:
Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes-including Pbrm1, Arid2, and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex-sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.
Insights
Tumor cells resist immunotherapy due to poorly understood mechanisms. Inactivating PBAF chromatin remodelers, like PBRM1, sensitizes cancer cells to T cell killing, enhancing immunotherapy effectiveness.
Area of Science:
- Immunology
- Cancer Biology
- Genetics
Background:
- Many human cancers exhibit resistance to immunotherapy, limiting treatment efficacy.
- The precise mechanisms driving tumor cell resistance to cytotoxic T cell-mediated killing remain largely unknown.
- Understanding these resistance mechanisms is crucial for developing more effective cancer immunotherapies.
Purpose of the Study:
- To identify genes and pathways involved in tumor cell resistance to cytotoxic T cells using a genome-wide screen.
- To investigate the role of the PBAF chromatin remodeling complex in mediating immunotherapy resistance.
- To explore the therapeutic potential of targeting PBAF components for overcoming treatment resistance.
Main Methods:
- Genome-scale CRISPR-Cas9 screening was employed to systematically inactivate genes in melanoma cells.
- Assessed the sensitivity of gene-inactivated cells to killing by cytotoxic T cells.
- Analyzed gene expression patterns and chemokine secretion in response to PBAF component inactivation.
- Correlated gene expression of PBAF components with T cell cytotoxicity markers in human cancers.
Main Results:
- Inactivation of over 100 genes, including PBAF components (PBRM1, ARID2, BRD7), sensitized melanoma cells to T cell-mediated killing.
- Loss of PBAF function enhanced tumor cell sensitivity to interferon-gamma and increased chemokine secretion, attracting T cells.
- Inactivating PBRM1 rendered treatment-resistant tumors responsive to immunotherapy.
- Reduced PBRM1 and ARID2 expression inversely correlated with T cell cytotoxicity gene expression in human cancers.
Conclusions:
- The PBAF chromatin remodeling complex is a key regulator of tumor cell sensitivity to cytotoxic T cells.
- Targeting PBAF components, such as PBRM1, can overcome immunotherapy resistance in certain cancers.
- These findings highlight PBAF as a potential therapeutic target for enhancing cancer immunotherapy outcomes.
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