Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

Somala Mohammed, Sujita Sukumaran, Pradip Bajgain, Norihiro Watanabe, Helen Heslop, Cliona M. Rooney, Malcolm Brenner, William E. Fisher, Ann M. Leen, Juan F. Vera

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

The adoptive transfer of T cells redirected to tumor-associated antigens via transgenic expression of chimeric antigen receptors (CARs) has produced tumor responses, even in patients with refractory diseases. To target pancreatic cancer, we generated CAR T cells directed against prostate stem cell antigen (PSCA) and demonstrated specific tumor lysis. However, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit CAR T cell persistence and function. Thus, to protect our cells from the immunosuppressive cytokine IL-4, we generated an inverted cytokine receptor in which the IL-4 receptor exodomain was fused to the IL-7 receptor endodomain (4/7 ICR). Transgenic expression of this molecule in CAR-PSCA T cells should invert the inhibitory effects of tumor-derived IL-4 and instead promote T cell proliferation. We now demonstrate the suppressed activity of CAR T cells in tumor-milieu conditions and the ability of CAR/ICR T cells to thrive in an IL-4-rich microenvironment, resulting in enhanced antitumor activity. Importantly, CAR/ICR T cells remained both antigen and cytokine dependent. These findings support the benefit of combining the 4/7 ICR with CAR-PSCA to treat pancreatic cancer, a PSCA-expressing tumor characterized by a dense immunosuppressive environment rich in IL-4.

Original languageEnglish (US)
Pages (from-to)249-258
Number of pages10
JournalMolecular Therapy
Volume25
Issue number1
DOIs
StatePublished - Jan 4 2017

Keywords

  • CAR
  • ICR
  • IL-4
  • IL-4R
  • IL-7R
  • PSCA
  • T cell therapy
  • chimeric antigen receptor
  • inhibitory cytokines
  • inverted cytokine receptor
  • pancreatic cancer
  • tumor microenvironment

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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