Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH

Abstract

Cellular immunotherapy has recently emerged as a fourth pillar in cancer treatment co-joining surgery, chemotherapy and radiotherapy. Where, the discovery of immune checkpoint blockage or inhibition (ICB/ICI), anti-PD-1/PD-L1 and anti-CTLA4-based, therapy has revolutionized the class of cancer treatment at a different level. However, some cancer patients escape this immune surveillance mechanism and become resistant to ICB-therapy. Therefore, a more advanced or an alternative treatment is required urgently. Despite the functional importance of epitranscriptomics in diverse clinico-biological practices, its role in improving the efficacy of ICB therapeutics has been limited. Consequently, our study encapsulates the evidence, as a possible strategy, to improve the efficacy of ICB-therapy by co-targeting molecular checkpoints especially N6A-modification machineries which can be reformed into RNA modifying drugs (RMD). Here, we have explained the mechanism of individual RNA-modifiers (editor/writer, eraser/remover, and effector/reader) in overcoming the issues associated with high-dose antibody toxicities and drug-resistance. Moreover, we have shed light on the importance of suppressor of cytokine signaling (SOCS/CISH) and microRNAs in improving the efficacy of ICB-therapy, with brief insight on the current monoclonal antibodies undergoing clinical trials or already approved against several solid tumor and metastatic cancers. We anticipate our investigation will encourage researchers and clinicians to further strengthen the efficacy of ICB-therapeutics by considering the importance of epitranscriptomics as a personalized medicine.

CISH Expression Is Associated with Metastasis-Free Interval in Triple-Negative Breast Cancer and Refines the Prognostic Value of PDL1 Expression

“…The co-targeting of cell surface immune checkpoint proteins (PD1 and PDL1) along with intracellular checkpoint molecules such as CISH is a promising approach [ 12 ], and might improve the results of ICIs in TNBC. Our objective was to document CISH expression in a large series of TNBC clinical samples and to search for correlations with tumor features and an eventual synergy with PDL1 expression.…”

“…However, not all patients derive benefit from these ICIs dedicated to improving antitumor cytotoxic immune responses, and many patients develop resistance to these treatments. These limitations emphasize the need to identify new cells and molecules that could be exploited in the next generation of immunotherapy [ 12 ].…”

10th Anniversary of Cells: Advances in Cellular Immunology—Regulation of Autoimmune Response and Antitumor Reactivity: Are They Two Side of the Same Coin?

“…Furthermore, Kumar and colleagues contributed a new approach to improve the efficacy of ICI therapy by co-targeting molecular machineries involved in the modifications of specific RNA to overcome toxicities and drug resistance to antibodies to immune-checkpoint receptors. That epitranscriptomics and general epigenetic molecular mechanisms can play an essential role in determining the cell fate in development and differentiation is becoming increasingly clear [ 11 ]. Joyce Taylor-Papadimitriou and Joy M. Burchell have clearly shown the changes occurring in cancer determined by histone methylases and demethylases [ 12 ].…”

YTHDF2 promotes intrahepatic cholangiocarcinoma progression and desensitises cisplatin treatment by increasing CDKN1B mRNA degradation

“…Epigenetic alterations play vital roles in tumourigenesis, chemoinsensitivity and anti‐tumour immunity. 7 , 8 , 9 N6‐methyladenosine (m 6 A) modification is the most abundant mRNA modification in eukaryotes, occurring in ∼30% of transcripts at the whole genome level. 10 m 6 A modification is dynamic and reversible and regulated by methylases, demethylases, and specific ‘reader’ proteins.…”