Leveraging the tug-of-war with genomic retroelements to enhance immunotherapy of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a dismal 5-year survival rate of less than 10%.1 Despite significant advances in cancer treatment over the past decades, PDAC has stubbornly defied progress, with most patients showing limited response to standard chemotherapy regimens. Perhaps most disappointingly, the revolutionary success of immunotherapy in various cancer types has not translated to PDAC, with checkpoint inhibitors and other immunomodulatory strategies showing dismally low response rates.2 This lack of efficacy is thought to be largely due to the characteristic PDAC tumour microenvironment (TME) that contributes to make this cancer immunologically ‘cold’.3 Characterised by a dense stromal compartment, low T cell infiltration and an overall immunosuppressive microenvironment, PDACs present a formidable barrier to the immune system that ultimately explains the inefficiency of current immunotherapeutic approaches. Whether and to what extent strategies can be identified to convert these ‘cold’ tumours into ‘hot’ ones and ultimately improve immune checkpoint blockade (ICB) efficacy in PDAC remains to be determined. One such strategy leverages the impact of epigenetic regulators in the control of genomic transposable elements, which comprise retrotransposons (or retroelements, including endogenous retroviruses, ERVs) and DNA transposons.4 Indeed, one …