RIPK3 inhibition prevents KRAS mutant p53 deficient lung tumor progression by impeding MDSCs
Jayakumar, A.
Show abstract
KRAS mutant p53 deficient (KP) non-small cell lung carcinoma (NSCLC) lacks targeted therapies. Existing treatments for lung cancer cause resistance and result in toxicities requiring novel effective therapies. By targeting mechanisms causing resistance such as myeloid derived suppressor cells (MDSCs), KP tumors could be inhibited. MDSCs are functionally diverse and suppress T cells in many cancers. RIPK3, a cell death inducing enzyme, also functions as a signaling component producing cytokines that mediate the suppressive function of MDSCs. Partial deletion of RIPK3 in myeloid cells reduced KP tumor growth. This also reduced accumulation of MDSCs with a consistent increase in antigen specific IFN{gamma} producing CD8 T cells. Inhibiting RIPK3 with a small molecule inhibitor such as GSK 872 effectively reduces RIPK3 activity in myeloid cells including MDSCs and reduces growth of small and large KP tumors. GSK 872 in combination with checkpoint inhibitors such as anti PD-1 and anti CTLA-4 further decreased KP tumor size. Together, our findings show that inhibiting RIPK3 in MDSCs is effective in inhibiting KP NSCLC and is a viable therapeutic option for improving existing immunotherapeutic treatments.
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