Exposure of tumor cells to the PARP-1 inhibitor Olaparib stimulates NK cell and macrophage effector functions

TROTTA, ALDANA; REGGE, MARÍA VICTORIA; FRIEDRICH, ADRIÁN D.; SIERRA, JESSICA M.; LOZADA MONTANARI, BELEN C.; RUBINSZTAIN, NATALIA; SANTILLI, M. CECILIA; GANTOV, MARIANA; ERRAMOUSPE, JULIETA; SECCHIARI, FLORENCIA; DOMAICA, CAROLINA I.; FUERTES, MERCEDES B.; ZWIRNER, NORBERTO W.

Mar del Plata

Congreso; Reunión Conjunta SAIC SAI FAIC SAFIS; 2022

Olaparib belongs to a novel set of drugs called PARP (poly ADP-ribose polymerase)-1 inhibitors (PARPi) that induce synthetic lethality in several types of tumor cells regardless its BCRA mutation status. Although the effect of PARP-1 inhibition in tumor cells is well known, the consequences of tumor cell exposure to PARPi on immune cells that usually constitute the tumor microenvironment (TME) remains ill-defined. Consequently, the aim of this work was to explore the effect of Olaparib on tumor cell elimination by NK cells and phagocytosis by macrophages. To broaden the potential Olaparib indications for tumor treatment and taking into consideration that effects on antitumor immunity has been reported beyond the induction of synthetic lethality, several human tumor cell lines were treated with subapoptotic doses (1 or 2.5 µM) of Olaparib for 48 h and NK cell degranulation was assessed by flow cytometry (FC). We observed that pre-treatment of Raji cells with Olaparib increased NK cell degranulation and this effect was not observed with the solid tumor cell lines HCT116 and 786-O. We assessed whether this effect was due to an upregulation of NKG2D ligands (NKG2DLs) upon treatment with Olaparib. By FC we observed that expression of NKG2DLs remained unaffected in 786-O, ACHN, SN12c, HCT116, HT-29, U937, SKBR3, MCF-7 and T47D cell lines but MICA and MICB expression was increased in K562 cells, while MICA, MICB, ULBP-3 and ULPB-4 expression was increased in Raji cells. Accordingly, NK cell degranulation in response to Olaparib-treated Raji cells was NKG2D-dependent. In addition, Raji cells treated with Olaparib for 48 h were also phagocytosed more efficiently by macrophages, as assessed by FC (p