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Updated: Dec 17, 2025
Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes
Published on: May 23, 2025
CRISPR-based screens uncover determinants of immunotherapy response in multiple myeloma
Poornima Ramkumar1, Anthony B Abarientos1, Ruilin Tian1
1Institute for Neurodegenerative Diseases and.
Abstract:
Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference- and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell surface expression of the multiple myeloma immunotherapy antigen B-cell maturation antigen (BCMA). We discovered that pharmacologic inhibition of HDAC7 and the Sec61 complex increased cell surface BCMA, including in primary patient cells. Pharmacologic Sec61 inhibition enhanced the antimyeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference chimeric antigen receptor T cells (CAR-T cells) coculture screen enabled us to identify both antigen-dependent and antigen-independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study shows the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.
Insights
Researchers identified ways to increase B-cell maturation antigen (BCMA) on cancer cells, potentially restoring immunotherapy effectiveness. Inhibiting HDAC7 and Sec61 boosted BCMA levels and improved treatment outcomes in multiple myeloma models.
Area of Science:
- Cancer immunotherapy
- Functional genomics
- Multiple myeloma therapeutics
Background:
- Immunotherapy resistance in cancer frequently arises from decreased antigen expression on tumor cells.
- Restoring target antigen levels on cancer cells can re-sensitize them to immunotherapy.
- B-cell maturation antigen (BCMA) is a key immunotherapy target in multiple myeloma.
Purpose of the Study:
- To systematically identify genetic pathways regulating cell surface BCMA expression using CRISPR screening.
- To discover novel therapeutic targets for enhancing BCMA expression and immunotherapy efficacy.
- To investigate mechanisms of response and resistance to BCMA-targeted chimeric antigen receptor T cell (CAR-T cell) therapy.
Main Methods:
- CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) functional genomics screens.
- Pharmacologic inhibition of identified pathways (HDAC7, Sec61 complex).
- BCMA-targeted antibody-drug conjugate efficacy assessment.
- CRISPRi-based CAR-T cell coculture screens in multiple myeloma models.
Main Results:
- Pharmacologic inhibition of HDAC7 and the Sec61 complex significantly increased cell surface BCMA expression.
- Increased BCMA levels were observed in primary patient-derived multiple myeloma cells.
- Sec61 complex inhibition enhanced the anti-myeloma activity of a BCMA-targeted antibody-drug conjugate.
- CRISPR screens identified both antigen-dependent and -independent factors influencing CAR-T cell therapy response.
Conclusions:
- Targeting HDAC7 and the Sec61 complex represents a promising strategy to enhance BCMA expression for immunotherapy.
- CRISPR-based functional screens are powerful tools for uncovering mechanisms of immunotherapy response and resistance.
- This study provides a foundation for developing combination therapies to overcome immunotherapy resistance in multiple myeloma.
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