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Kundu K, Ghosh S, Sarkar R, Edri A, Brusilovsky M, Gershoni-Yahalom O, Yossef R, Shemesh A, Soria JC, Lazar V, Joshua BZ, Campbell KS, Elkabets M, Porgador A
Inhibition of the NKp44-PCNA Immune Checkpoint Using a mAb to PCNA
Cancer Immunol Res (2019) 7:1120-1134.
Monoclonal antibody (mAb)-based blocking of the immune checkpoints involving the CTLA4-B7 and PD1-PDL1 inhibitory axes enhance T cell-based adaptive immune responses in cancer patients. We show here that antitumor responses by natural killer (NK) cells can be enhanced by a checkpoint-blocking mAb, 14-25-9, that we developed against proliferating cell nuclear antigen (PCNA). PCNA is expressed on the surface of cancer cells and acts as an inhibitory ligand for the NK cell receptor, NKp44-isoform1. We tested for cytoplasmic and membrane-associated PCNA by FACS- and ImageStream-based staining of cell lines and immunohistochemistry of human cancer FFPE tissues. The mAb 14-25-9 inhibited binding of chimeric NKp44 receptor to PCNA and mostly stained the cytoplasm and membrane of tumor cells, whereas commercial antibody (clone PC10) stained nuclear PCNA. NK functions were measured using ELISA-based IFNgamma secretion assays and FACS-based killing assays. The NK92-NKp44-1 cell line and primary human NK cells showed increased IFNgamma release upon co-incubation with mAb 14-25-9 and various solid tumor cell lines and leukemias. Treatment with 14-25-9 also increased NK cytotoxic activity. In vivo efficacy was evaluated on patient-derived xenografts (PDX)-bearing NSG mice. In PDX-bearing mice, intravenous administration of mAb 14-25-9 increased degranulation (CD107a expression) of intratumorally-injected patient-autologous or allogeneic NK cells as well as inhibited tumor growth when treated long term. Our study describes a mAb against the NKp44-PCNA innate immune-checkpoint that can enhance NK cell antitumor activity both in vitro and in vivo.
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Publication Date: 2019-07-01.
Last updated on Sunday, August 09, 2020