PRMT5 highly expressed on CD16 + CD56- natural killer cells is correlated with NK cells exhaustion in colorectal cancer mesenchyme.

Objective: To investigate the relationships between changes in the phenotype of natural killer cells (NK cells) in the microenvironment of colorectal cancer (CRC) and the expression of important immune checkpoints. To assess the expression level of CD16 bright CD56 negative (CD16 + CD56-) NK cell-associated immune checkpoints, including protein arginine methyltransferase 5 (PRMT5) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), single-immunoglobulin interleukin-1-related receptor (SIGIRR), in CRC mesenchyme.

Methods: A total of 194 patients who were diagnosed with CRC were screened. The percentage of NK cells and the expression levels of their surface receptors, including PRMT5, CD56, CD69, TIGIT, CD16, IFN-γ, and SIGIRR, in the tumor microenvironment (TME) of CRC were assessed. Immunohistochemical staining, multiplex immunohistochemistry, and single-cell sequencing were performed.

Results: Compared with normal mesenchyme, NK cells were less in CRC mesenchyme. The percentage of CD16 + CD56- NK cells in tumor mesenchyme was significantly higher, the number of CD16 + NK cells was more, and the number of CD56 + NK cells was less in CRC mesenchyme. High expression of TIGIT and PRMT5 expression affected the progression of CRC. The expression of PRMT5 and SIGIRR expression was significantly increased in CD16 + CD56- NK cells, and both genes were identified as important morbidity factors. PRMT5 and SIGIRR may contribute to the phenotype changes of NK cells in CRC.

Conclusion: The microenvironment of CRC is in an immunosuppressive state characterized mainly by high expression of TIGIT, CD16, PRMT5, and SIGIRR; low expression of CD56, IFN-γ, and CD69; significantly decreased percentage of CD56 + NK cells; and significantly increased percentage of CD16 + CD56- NK cells with weakened killing ability. PRMT5 and TIGIT may be closely related to the formation of CD16 + CD56- NK cells with weakened killing ability.