Macrophages and CD8þ T cells mediate the antitumor efficacy of combined CD40 ligation and imatinib therapy in gastrointestinal stromal tumors

Jennifer Q. Zhang, Shan Zeng, Gerardo A. Vitiello, Adrian M. Seifert, Benjamin D. Medina, Michael J. Beckman, Jennifer K. Loo, Juan Santamaria-Barria, Joanna H. Maltbaek, Nesteene J. Param, John A. Moral, Julia N. Zhao, Vinod Balachandran, Ferdinand Rossi, Cristina R. Antonescu, Ronald P. DeMatteo

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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 germ-line mutation in Kit exon 11. Activated TAMs had greater TNFa production and NFkB 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 CD8þ T cells, but not on CD4þ 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.

Original languageEnglish (US)
Pages (from-to)434-447
Number of pages14
JournalCancer immunology research
Volume6
Issue number4
DOIs
StatePublished - Apr 2018

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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