Stronger Anti-Tumour Immunity in Colorectal Cancers via Inhibition of Protein Phosphatase 2A

To better understand microsatellite-instable (MSI) tumours as a key to overcoming colorectal cancers (CRCs), this study shows that the inhibition of protein phosphatase 2A (PP2A) could lead to the loss of DNA mismatch repair (MMR) genes (i.e. causing MMRd), resulting in the conversion of microsatellite-stable (MSS) into MSI tumours. The PP2A inhibition brings about the conversion via two different pathways, i.e. by increasing retinoblastoma protein phosphorylation and by increasing histone deacetylase (HDAC)2 phosphorylation. Moreover, the inactivation of PP2A also enhances MSI tumours’ response to immune checkpoint blockade (ICB). In short, PP2A inhibition initiates neoantigen production, increases cytotoxic T cell infiltration and improves response to ICB. These results were obtained from animal models as well as human cancer cell lines and tissue array. In order to materialise an effective therapy based on the findings, future studies should investigate the effect of mRNA dysregulation or mutations of the genes on the adaptive and acquired resistance to ICB.

15% of sporadic colorectal cancers (CRCs) are closely associated to microsatellite-instable (MSI) tumours with defective DNA mismatch repair (MMR). Compared to microsatellite-stable (MSS) tumours, focusing on the mechanism of MSI tumours development is a more practical strategy as MSI tumours exhibit better prognosis and response to immune checkpoint blockade (ICB) (i.e. a type of immunotherapy drug). Studies show that both CRC and non-CRC patients with MMR deficiency (MMRd) have better responses to programmed death 1 (PD-1) ICB therapy. These findings support the need to focus on MSI tumours even though the molecular mechanisms have yet to be confirmed. Meanwhile, although protein phosphatase 2A (PP2A)-targeted anti-tumour therapies have received significant attention, the anti-tumour effects of activating or inhibiting PP2A activity is uncertain. Furthermore, the number of studies on PP2A’s tumour-intrinsic signaling and response to ICB are still scanty. Therefore, this research aims to achieve two goals, i.e. to investigate the mechanism of MMRd and to examine the effect of PP2A inhibition on the conversion of MSS to MSI tumours. Other than solving the previously unanswered questions, the output of this study provides valuable insights to the possible feasible ways to overcome cancers by focusing on PP2A.

In 2020, CRC was the second most common cause of cancer death worldwide, causing almost 1 million deaths. It was the third most common cancer in men but the second most common cancer in women, after breast cancer. The in-depth discussion on the potential of PP2A inhibition in fighting CRC opens up an avenue for the realisation of new treatments for CRC. With better knowledge base and more effective therapy, tremendous amount of CRC patients with will stand higher chance to survive (UNSDG 3: Good Health & Well-being).