CRISPR Reveals Ways to Improve Immunotherapy


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Cancerous cells can become resistant to immunotherapy as the cancer cells can lose expression of the target antigen on the cell surface. Additional treatments can be used in conjunction with immunotherapy to increase the expression of the target antigen and therefore improve the efficiency of the immunotherapy.


A study was published in bioRxiv, researchers used CRISPR based screening to uncover pathways that affect the cell surface expression of BCMA, the immunotherapy target antigen for multiple myeloma. Scientists found that BCMA expression was regulated by many genes. Knocking out some of the gamma-secretase complex subunits increased BCMA on the cell surface, the gamma-secretase complex is involved in cleaving BCMA to a soluble form. Furthermore, knockouts of the HDAC7 gene (transcription regulation), or the SEC61A1 gene (part of the Sec61 complex) also increased BCMA on the cell surface.


ADC therapy which stands for antibody-drug conjugate is an immunotherapy drug. ADCs are made of an antibody joined to a toxic drug that can kill cancerous cells. The ADCs are able to target a specific antigen such as BCMA. When scientists used a gamma-secretase inhibitor or a Sec61 inhibitor, the BCMA on the cell surface increased as expected, but then the efficiency of the ADC immunotherapy had substantially increased too. Therefore, individuals may be able to take drugs such as a gamma-secretase inhibitor or a Sec61 inhibitor in conjunction with immunotherapy to improve the outcome.


Interestingly, the researchers also found pathways that are antigen-independent which can alter the responsiveness of cancerous cells to immunotherapy. These include intercellular adhesion molecule 1 (ICAM1) that is involved in activating T cells and DNA fragmentation factor subunit alpha (DFFA) that activates caspases to induce apoptosis. These pathways need to be further researched to find out how exactly they alter sensitivity to immunotherapy. In conclusion, CRISPR based screening tools are very important and can help to discover novel pathways that could further improve the efficiency of immunotherapy one day.




Reference

https://www.biorxiv.org/content/10.1101/833707v3.full.pdf

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