Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer

Pat Gulhati, Aislyn Schalck, Shan Jiang, Xiaoying Shang, Chang Jiun Wu, Pingping Hou, Sharia Hernandez Ruiz, Luisa Solis Soto, Edwin Parra, Haoqiang Ying, Jincheng Han, Prasenjit Dey, Jun Li, Pingna Deng, Emi Sei, Dean Y. Maeda, John A. Zebala, Denise J. Spring, Michael Kim, Huamin WangAnirban Maitra, Dirk Moore, Karen Clise-Dwyer, Y. Alan Wang, Nicholas E. Navin, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.

Original languageEnglish (US)
Pages (from-to)62-80
Number of pages19
JournalNature Cancer
Volume4
Issue number1
DOIs
StatePublished - Jan 2023

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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