Options for the development of colorectal cancer immunotherapy

Abstract

In colorectal cancer immunotherapy, the use of antibodies against the PD-1/PD-L1 checkpoints showed low efficacy and the development of a number of side effects with damage to the liver, lung, and thyroid gland. For this reason, to stimulate the antitumor immune response, it is necessary to search for other targets, which can be used as retroelements. Epigenetic activation of their expression with inhibitors of histone methyltransferases and deoxyribonucleic acids (DNA) leads to the formation of double-stranded ribonucleic acids (RNA) that stimulate the antiviral response of interferon, which causes apoptosis of tumor cells. This method of viral mimicry shows an objective response in colorectal cancer and other malignant neoplasms. However, activation of retrotransposons is an inducer of carcinogenesis and a necessary condition for clonal evolution and the development of chemoresistance. Therefore, the most rational combination of the method of viral mimicry is with selective inhibition of retroelements involved in the pathogenesis of colorectal cancer. For this purpose, specific miRNAs, that recruit DNA methyltransferases to the loci of the location of retroelements due to the complementarity of nucleotide sequences, which is due to their evolutionary relationship, can be used. An analysis of the scientific literature revealed 28miRNAs derived from transposons and associated with colorectal cancer, some of which exhibit oncosuppressive activity, while others exhibit oncogenic activity. These miRNAs can be used as guides for epigenetic effects on retroelements involved in colorectal cancer carcinogenesis.