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

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

Mar del Plata

Congreso; 70ª Reunión Anual de la Sociedad Argentina de Inmunología y 3rd French-Argentine Immunology Congress (FAIC); 2022

Sociedad Argentina de Inmunología

Olaparib belongs to a novel set of drugs called PARP (poly ADP-ribose polymerase)-1 inhibitors (PARPi) that induce synthetic lethality in BCRA-mutated tumor cells. 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 is to explore the effect of Olaparib on the capacity of NK cells to eliminate tumor cells and the ability of macrophages to phagocytose tumor cells. In order to extend/broaden the 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 response was assessed by flow cytometry. Our results showed that pre-treatment of Raji with Olaparib increase the induction of NK cell degranulation and this effect was not observed with other cell lines tested. We wondered whether this results were due to an upregulation of NKG2D ligands upon treatment with Olaparib. In order to answer that, NKG2D ligands expression was analyzed by flow cytometry. Our results indicate that treatment with Olaparib did not alter NKG2D-ligands expression on 786-O, ACHN, SN12c, HCT116, HT-29, U937, SKBR3, MCF-7 and T47D cell lines. Whereas, it increased MICA and MICB expression on K562 and MICA, MICB, ULBP-3 and ULPB-4 expression on Raji cell lines, which could explain our degranulation results. In line with these results, Olaparib-treated Raji fail to induce NK cell degranulation in presence of NKG2D inhibitor ID11. In addition, we further evaluated the immune response against Olaparib-treated Raji cells. For this, Raji cells were treated with Olaparib for 48 h and its phagocytosis by macrophages was assessed by flow cytometry. Our results showed that treatment with Olaparib also induced an increase in Raji phagocytosis by macrophages. In line with this result, we demonstrated that Calreticulin and Anexine V, two well known “eat-me” signals, are upregulated in Raji cell line upon treatment with Olaparib. In summary, this work demostrate that Olaparib induces a immunogenic profile in Raji cells which promote the response of both Macrophages and NK cells.