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

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

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias. SAIC. SAI&FAIC. SAFIS. 2022; 2022

SAIC. SAI&FAIC. SAFIS.

Olaparib belongs to a novel set of drugs called PARP (poly ADP-ribose polymerase)-1inhibitors (PARPi) that induce synthetic lethality in several types of tumor cells regardless itsBCRA 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 thetumor microenvironment (TME) remains ill-defined. Consequently, the aim of this work wasto explore the effect of Olaparib on tumor cell elimination by NK cells and phagocytosis bymacrophages. To broaden the potential Olaparib indications for tumor treatment and takinginto consideration that effects on antitumor immunity has been reported beyond the inductionof synthetic lethality, several human tumor cell lines were treated with subapoptotic doses (1or 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 celldegranulation 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 remainedunaffected in 786-O, ACHN, SN12c, HCT116, HT-29, U937, SKBR3, MCF-7 and T47D celllines 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 celldegranulation 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 bymacrophages, as assessed by FC (p