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

TROTTA, ALDANA; REGGE, MARÍA VICTORIA; FRIEDRICH, ADRIÁN; SIERRA, JESSICA MARIEL; LOZADA MONTANARI, BELEN; RUBINZSTEIN, NATALIA; SANTILLI, MARÍA CECILIA; GANTOV, MARIANA; ERRAMOUSPE, JULIETA; SECCHIARI, FLORENCIA; DOMAICA, CAROLINA INÉS; FUERTES, MERCEDES BEATRIZ; ZWIRNER, NORBERTO WALTER

MAr del Plara

Congreso; Reunion anual de Biociencias; 2022

SAI

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 regardlessits BCRA mutation status. Although the effect of PARP-1 inhibition in tumor cells is wellknown, the consequences of tumor cell exposure to PARPi on immune cells that usuallyconstitute the tumor microenvironment (TME) remains ill-defined. Consequently, the aim ofthis work was to explore the effect of Olaparib on tumor cell elimination by NK cells andphagocytosis by macrophages. To broaden the potential Olaparib indications for tumortreatment and taking into consideration that effects on antitumor immunity has been reportedbeyond the induction of synthetic lethality, several human tumor cell lines were treated withsubapoptotic doses (1 or 2.5 µM) of Olaparib for 48 h and NK cell degranulation wasassessed by flow cytometry (FC). We observed that pre-treatment of Raji cells with Olaparibincreased NK cell degranulation and this effect was not observed with the solid tumor celllines HCT116 and 786-O. We assessed whether this effect was due to an upregulation ofNKG2D ligands (NKG2DLs) upon treatment with Olaparib. By FC we observed thatexpression 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 increasedin K562 cells, while MICA, MICB, ULBP-3 and ULPB-4 expression was increased in Rajicells. Accordingly, NK cell degranulation in response to Olaparib-treated Raji cells wasNKG2D-dependent. In addition, Raji cells treated with Olaparib for 48 h were alsophagocytosed more efficiently by macrophages, as assessed by FC (p