Alternative splicing of modulatory immune receptors in T lymphocytes: a newly identified and targetable mechanism for anticancer immunotherapy

Abstract

Alternative splicing (AS) is a mechanism that generates translational diversity within a genome. Equally important is the dynamic adaptability of the splicing machinery, which can give preference to one isoform over others encoded by a single gene. These isoform preferences change in response to the cell's state and function. Particularly significant is the impact of physiological alternative splicing in T lymphocytes, where specific isoforms can enhance or reduce the cells' reactivity to stimuli. This process makes splicing isoforms defining features of cell states, exemplified by CD45 splice isoforms, which characterize the transition from naïve to memory states. Two developments have accelerated the use of AS dynamics for therapeutic interventions: advancements in long-read RNA sequencing and progress in nucleic acid chemical modifications. Improved oligonucleotide stability has enabled their use in directing splicing to specific sites or modifying sequences to enhance or silence particular splicing events. This review highlights immune regulatory splicing patterns with potential significance for enhancing anticancer immunotherapy.

Keywords: T lymphocytes; alternative splicing; cancer; immune receptors; immunotherapy.

Figure 1

Alternative splicing patterns.

Figure 2

Mechanisms that lead to antagonistic or agonistic effects of soluble ectodomains derived from immune regulatory receptors. (A–E, mechanisms depicted).

Figure 3

Production of soluble receptors by alternative splicing or enzymatic cleavage. Of note, the intracellular part of a receptor remains only in the cleavage process. ECD, extracellular domain, TMD, transmembrane domain, ICD, intracellular domain.

Figure 4

Mechanisms of splicing disruption by mutations affecting the core spliceosome complex; splicing factors, or splicing recognition sites, altering the expression level of a single gene or creating new isoforms.

Figure 5

The principle of RNA splicing analysis using Nanopore long-reads or Ilumina short-reads, representing methods based on exon, isoform, or event.

Figure 6

Splice-switching oligonucleotide that enhances exon skipping and increases the expression of an alternative isoform.

Figure 7

Main chemical modifications of nucleic acids to improve the clinical applicability of oligonucleotides.