Abstract: Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the NK cell responses to CRC. Compared to conventional (c) NK cells, ML NK cells displayed increased IFN-γ production against both CRC cell lines and primary patient-derived CRC spheroids. ML NK cells also exhibited improved killing of CRC target cells in vitro in short-term and sustained cytotoxicity assays, as well as in vivo in NSG mice. Mechanistically, enhanced ML NK cell responses were dependent on the activating receptor NKG2D as its blockade significantly decreased ML NK cell functions. Compared to cNK cells, ML NK cells exhibited greater antibody-dependent cytotoxicity when targeted against CRC by cetuximab. ML NK cells from healthy donors and mCRC patients exhibited increased anti-CRC responses. Collectively, our findings demonstrate that ML NK cells exhibit enhanced responses against CRC targets, warranting further investigation in clinical trials for mCRC patients, including those who have failed ICB.
Competing Interests: M.M.B.-E. and T.A.F. are inventors on patent/patent applications (15/983,275, 62/963,971, and PCT/US2019/060005) licensed to Wugen Inc. and held/submitted by Washington University that involve ML NK cells. This results in potential royalties to M.M.B.-E., T.A.F., and Washington University from Wugen Inc. M.M.B.-E. has equity, consulting, and royalty interest in Wugen Inc. T.A.F. reports research funding from HCW Biologics Inc., Wugen, Affimed and the NIH during the conduct of the study. T.A.F. has equity, research funding, consulting, and royalty interest in Wugen Inc. Unrelated to this work, T.A.F. also reports consulting for Affimed, AI Proteins, Smart Immune, and advises (equity interest) Indapta and OrcaBio. Unrelated to this work, J.A.F. is an inventor on patent/patent application (WO 2019/152387, US 63/018,108) licensed to Kiadis Inc. and held/submitted by Nationwide Children’s Hospital on TGF-β resistant, expanded NK cells. Unrelated to this work, J.A.F. has a monoclonal antibody unrelated to the present work licensed to EMD Millipore. Unrelated to this work, C.C.C. reports equity in Pionyr Immunotherapeutics. Unrelated to this work, D.A.R.-G. receives consulting fees from Cartography Inc. All other authors declare that they have no competing interests.
(© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)
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