Inhibition of RNA-m6A Methylation in Breast Cancer Cells Carrying TP53 R273H Mutant Reactivates Natural Killer Cells for Anticancer Immunity

Abstract

Oncogenic p53 mutant proteins not only promote cancer cell proliferation but also evade immune destruction for tumor progression. Besides hijacking immune checkpoints, p53 mutants in cancer cells may deactivate anticancer immune cells for evasion. Herein, we report that p53 R273H mutation in human breast cancer cells deactivated natural killer (NK) cells in immune evasion; conversely inhibition of RNA methylation with neplanocin A (NPC) reactivated NK cells and reinforced cytotoxicity against cancer. Human MDA-MB-468 breast cancer cells, which carry homozygous p53 R273H, significantly deactivated NK-92 MI cells, while either MCF-7 cancer cells or MCF-10A noncancerous cells, both are wild-type p53, activated NK cells to produce interferon-γ (IFN-γ) production in co-cultures. Consistently, NK cytotoxicity to tumor organoids induced by MCF-7 cells was approximately 4-fold higher than MDA-MB-468 cells. Interestingly, inhibition of RNA m6A methylation of MDA-MB-468 cells with NPC markedly reactivated proliferation of NK-92 MI cells, increased IFN-γ levels and destructed tumor organoids. Further mechanistic study showed that inhibition of RNA m6A-modification enhanced p53-associated NKG2D ligands, including ULBP1 in cancer cells, to activate NK cells through NKG2D receptors in antitumor immunity. Altogether, our study suggests that targeting m6A methylation in p53 mutant-cancer cells can reactivate NK cell-based antitumor immunity.