Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

A new study published in Cell shows that splicing modulation in cancer cells results in the production of neoantigens, thus eliciting anti-tumour immunity. Splicing modulation using the drug indisulam inhibited tumour growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumour MHC class I. The study identified for the first time splicing modulation as source of immunogenic peptides and provided a means to enhance anti-tumour immune response that is readily translatable to the clinic.

But what does a tree have to do with all this? The repertoire of antigens shown on the surface of cancer cells (symbolised by the tree) stems from the pool of transcripts produced within the cell (the roots).When the tree is "fertilised" with a splicing modulator (i.e. Indisulam), splicing patterns are altered, hence the roots are overgrown and entangled, leading to the production of aberrant proteins. Some of these become neoantigens, the blooming flowers on the surface.

Neoantigens induced by splicing modulation are novel epitopes, presented exclusively on the surface of treated cells. These bright "flowers" can be readily recognised by the immune system and thus enhance the endogenous T-cell response against tumour cells.

Lu SX, De Neef E, Thomas JD, Sabio E, Rousseau B, Gigoux M, Knorr DA, Greenbaum B, Elhanati Y, Hogg SJ, Chow A, Ghosh A, Xie A, Zamarin D, Cui D, Erickson C, Singer M, Cho H, Wang E, Lu B, Durham BH, Shah H, Chowell D, Gabel AM, Shen Y, Liu J, Jin J, Rhodes MC, Taylor RE, Molina H, Wolchok JD, Merghoub T, Diaz LA Jr, Abdel-Wahab O, Bradley RK. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. Cell. 2021 Jul 22;184(15):4032-4047.e31. doi: 10.1016/j.cell.2021.05.038. Epub 2021 Jun 24. PMID: 34171309; PMCID: PMC8684350.

Link to the study

Press Release from Fred Hutch