Programmed cell death ligand 1 (PD-L1) regulates tumor initiating cell (TIC) generation by controlling the stemness gene Oct4 through mTORC1

• Published in: The Journal of immunology (1950) 2018-05, Vol.200 (1_Supplement), p.167-167.15
• Main Authors: Gupta, Harshita B., Deng, June, Clark, Curtis A., Drerup, Justin Michael, Wu, Bogang, Sareddy, Gangadhara, Hurez, Vincent, Vadlamudi, Ratna, Li, Rong, Curiel, Tyler J.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.200.Supp.167.15

TIC mediate tumor formation, drug resistance and relapse. We reported that PD-L1 promotes tumor mTORC1, and TIC number and functions. Knocking down PD-L1 reduced expression of stemness genes Oct4 and Nanog and the mTORC1 signaling component Raptor in B16 melanoma and ID8agg ovarian cancer (OC) cells. To understand how PD-L1 controls stemness, we treated control and PD-L1 KO (KO) B16 cells with rapamycin (mTORC1 inhibitor), PI3K inhibitor wortmannin, Notch inhibitor Compound E, and c-Myc inhibitor JQ1. Only rapamycin affected control and KO CD133+CD44+CD24+ TIC differentially (50% reduced TIC in control versus 0% in KO, p=0.0075). We over-expressed Oct4 in B16 but failed to get clones, so over-expressed it in ID8agg PD-L1lo cells (KI) and found that TICs (CD44+CD24+) had improved proliferation and 2-fold more TIC than PD-L1lo cells (p=0.015, p=0.018). We sorted ID8agg, PD-L1lo and KI TIC and cultured them in stem cell medium. KI TICs formed four-fold bigger spheres than PD-L1lo TIC (p