The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research. Previously known as our Top 10 Cancer Research Publications, it is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
Use the dropdown menu or ‘Previous’ and ‘Next’ buttons to navigate the list.
Yen, YT., Chien, M., Wu, PY. et al. Nat Commun 12, 7297 (2021).
doi: 10.1038/s41467-021-27620-x.
“This paper shows that we can make MSS tumors MSI with a small molecule PP2A inhibitor and thereby sensitize to checkpoint therapy. This could be a great synergy with immuno-oncology drugs.” EACR Board
Summary of findings
Microsatellite instability (MSI), a predictive biomarker of immune checkpoint blockade (ICB) response, is caused by mismatch repair deficiency (MMRd) through epigenetic silencing of the MMR genes. MSI is the first FDA-approved tissue-agnostic therapy, an anti-cancer treatment that targets a common genetic biomarker of cancer, regardless of tumour type. However, MSI tumours with MMRd account for only 15% of sporadic colorectal cancer, the tumour type with the highest prevalence of MSI, suggesting most cancer patients do not respond to ICB. Here, we report a mechanism of MMRd and demonstrate that protein phosphatase 2A (PP2A) deletion or inactivation converts microsatellite stability (MSS) tumours into MSI tumours through two orthogonal pathways: (i) by increasing retinoblastoma protein phosphorylation that leads to E2F and DNMT3A/3B expression with subsequent DNA methylation, and (ii) by increasing histone deacetylase (HDAC)2 phosphorylation that subsequently decreases H3K9ac levels and histone acetylation, which induces epigenetic silencing of MLH1. In mouse models of MSS and MSI colorectal cancers, triple-negative breast cancer and pancreatic cancer, PP2A inhibition triggers neoantigen production, cytotoxic T cell infiltration and ICB sensitization. Human cancer cell lines and tissue array confirm these signaling pathways. These data indicate the dual involvement of PP2A inactivation in silencing MLH1 and inducing MSI.
Future impact
Recent advances in immunotherapy have led to real breakthroughs in developing more effective and less toxic treatments for many cancers. Unfortunately, most cancer patients do not respond to ICB. There are widespread efforts to find pharmacologic and/or immunologic ways to turn unresponsive (‘cold’) tumours into responsive (‘hot’) tumours. Our data demonstrate that defective MMR can be induced by targeting PP2A both in vitro and in vivo, which leads to accumulation of mutational burden and increased neoantigens, which in turn trigger anti-tumour immune surveillance and sensitize tumours to ICB. Moreover, this strategy can be applied to multiple human tumour types.
