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Podoplanin (PDPN), a transmembrane sialomucin\u2010like glycoprotein, has been investigated as a diagnostic marker and therapeutic target for MPM. We previously generated and developed a PDPN\u2010targeting Ab reagent with high Ab\u2010dependent cellular cytotoxicity (ADCC) and complement\u2010dependent cytotoxicity (CDC). However, the effects of anti\u2010PDPN Abs on various tumor\u2010infiltrating immune cells and their synergistic effects with ICIs have remained unclear. In the present study, we established a novel rat\u2013mouse chimeric anti\u2010mouse PDPN IgG<jats:sub>2a<\/jats:sub> mAb (PMab\u20101\u2010mG<jats:sub>2a<\/jats:sub>) and its core\u2010fucose\u2010deficient Ab (PMab\u20101\u2010mG<jats:sub>2a<\/jats:sub>\u2010f) to address these limitations. We identified the ADCC and CDC activity of PMab\u20101\u2010mG<jats:sub>2a<\/jats:sub>\u2010f against the PDPN\u2010expressing mesothelioma cell line AB1\u2010HA. The antitumor effect of monotherapy with PMab\u20101\u2010mG<jats:sub>2a<\/jats:sub>\u2010f was not sufficient to overcome tumor progression in AB1\u2010HA\u2010bearing immunocompetent mice. However, PMab\u20101\u2010mG<jats:sub>2a<\/jats:sub>\u2010f enhanced the antitumor effects of CTLA\u20104 blockade. Combination therapy with anti\u2010PDPN Ab and anti\u2010CTLA\u20104 Ab increased tumor\u2010infiltrating natural killer (NK) cells. The depletion of NK cells inhibited the synergistic effects of PMab\u20101\u2010mG<jats:sub>2a<\/jats:sub>\u2010f and CTLA\u20104 blockade in\u00a0vivo. These findings indicated the essential role of NK cells in novel combination immunotherapy targeting PDPN and shed light on the therapeutic strategy in advanced MPM.<\/jats:p>","DOI":"10.1111\/cas.16046","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T04:25:30Z","timestamp":1703651130000},"page":"357-368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antipodoplanin antibody enhances the antitumor effects of <scp>CTLA<\/scp>\u20104 blockade against malignant mesothelioma by natural killer cells"],"prefix":"10.1111","volume":"115","author":[{"given":"Hiroto","family":"Yoneda","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine and Rheumatology Tokushima University  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Mitsuhashi","sequence":"additional","affiliation":[{"name":"Department of Respiratory 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