Macrophages and CD8+ T Cells Mediate the Antitumor Efficacy of Combined CD40 Ligation and Imatinib Therapy in Gastrointestinal Stromal Tumors

Cancer Immunology Research
Jennifer Q ZhangRonald P DeMatteo

Abstract

Tyrosine kinase inhibition of gastrointestinal stromal tumors (GIST) is effective but typically culminates in resistance and is rarely curative. Immunotherapy has potential application to GIST, as we previously showed that T-cell checkpoint blockade increases the antitumor effects of imatinib. Here, we showed that ligation of CD40 using an agonistic antibody (anti-CD40) activated tumor-associated macrophages (TAMs) in vivo in a knock-in mouse model of GIST harboring a germline mutation in Kit exon 11. Activated TAMs had greater TNFα production and NFκB signaling and directly inhibited tumor cells in vitro Anti-CD40 required concomitant therapy with imatinib for efficacy and depended on TAMs, and to a lesser extent CD8+ T cells, but not on CD4+ T cells or B cells. In an analysis of 50 human GIST specimens by flow cytometry, we found that CD40 was expressed on human TAMs and tumor cells yet was downregulated after response to imatinib. CD40 ligation did not have a direct inhibitory effect on human GIST cells. Our findings provide the rationale for combining anti-CD40 and tyrosine kinase inhibition to treat human GIST. Cancer Immunol Res; 6(4); 434-47. ©2018 AACR.

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Citations

Feb 15, 2019·The Journal of Clinical Investigation·Gerardo A VitielloRonald P DeMatteo
Aug 14, 2019·Human Vaccines & Immunotherapeutics·David M RichardsChristian Merz
Sep 25, 2019·International Journal of Molecular Sciences·Chloé LaplagneMary Poupot
Jul 28, 2020·Cancers·Anna Maria MalfitanoGiuseppe Portella
Dec 15, 2020·Expert Opinion on Pharmacotherapy·Antoine Italiano
Dec 19, 2020·Cancer Cell·Giulia PetroniLorenzo Galluzzi
Jan 29, 2021·Journal for Immunotherapy of Cancer·Chunxiao LiUNKNOWN Senior Correspondence
Mar 3, 2021·Cancer Immunology Research·Mengyuan LiuRonald P DeMatteo

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