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The Transformative Potential of Splice Isoforms
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing is a groundbreaking technique that allows for precise alterations in DNA, offering immense potential for cancer research and treatment. Originating from a defense mechanism found in bacteria, scientists use the CRISPR-Cas9 system to cut specific locations in the genome and introduce desired changes.
A potential benefit of CRISPR technology is the ability to understand the genetic factors driving cancer, develop better models of research, and potentially develop new therapies.
A particular area of interest has been the immune receptor SLAMF6. Our data-driven research project has explored its multiple splice isoforms, particularly focusing on its V-domain. This exploration revealed that while the canonical receptor has an inhibitory effect on T-cell activation, a shorter splice isoform, SLAMF6Δ17-65, presents a potent agonistic effect
Our novel approach focuses on deciphering immune cell-specific cfDNA methylation markers present in the urine. This pioneering methodology taps into the field of cancer epigenetics, focusing on modifications that control gene expression rather than altering the DNA sequence itself.
By investigating these markers, we hope to better understand the dynamic interactions between the immune system and cancer, and detect crucial changes indicative of the disease’s progression.
Alongside this, we’re also phenotyping the immune sediment found in urine for exhaustion markers. Immune cell exhaustion is a state of dysfunction that commonly occurs in the cancer microenvironment, leading to reduced immune cell response to cancer cells.
This research has uncovered a fascinating dynamic between SLAMF6 splicing isoforms, suggesting a yin-yang relationship where a balance between agonistic and antagonistic isoforms can shift with receptor activation. This concept, if proven across other immune regulatory receptors, could revolutionize our understanding of immune responses and open new avenues for more effective cancer treatment.
Our research team at HCRI continues to explore this intriguing balance and the wider implications of our findings, driven by our commitment to advancing cancer treatment and the global understanding of this complex disease
Hajaj E et al.: Alternative Splicing of the Inhibitory Immune Checkpoint Receptor SLAMF6 Generates a Dominant Positive Form, Boosting T-cell Effector Functions. Cancer Immunol Res. 2021 Jun;
