Ma and Xu et al. found that TCR stimulation of memory-like T cells upregulated IL-23R and the IL-23α p19 subunit, but surprisingly not the IL-12β p40 subunit of IL-23. In xenograft and syngeneic cancer models, p40-transduced CAR (CAR.p40) or antigen-specific TCR T cells secreted IL-23 upon CAR or TCR stimulation, showed enhanced proliferation and persistence, upregulated STAT3-responsive genes, and conferred enhanced tumor control and survival. IL-23 produced by CAR.p40 T cells acted in an autocrine fashion, with limited effects on bystander cells. CAR.p40 cells had better efficacy and safety than CAR T cells expressing IL-18 or IL-15.
Contributed by Anna Scherer
ABSTRACT: Cytokines that stimulate T cell proliferation, such as interleukin (IL)-15, have been explored as a means of boosting the antitumor activity of chimeric antigen receptor (CAR) T cells. However, constitutive cytokine signaling in T cells and activation of bystander cells may cause toxicity. IL-23 is a two-subunit cytokine known to promote proliferation of memory T cells and T helper type 17 cells. We found that, upon T cell antigen receptor (TCR) stimulation, T cells upregulated the IL-23 receptor and the IL-23alpha p19 subunit, but not the p40 subunit. We engineered expression of the p40 subunit in T cells (p40-Td cells) and obtained selective proliferative activity in activated T cells via autocrine IL-23 signaling. In comparison to CAR T cells, p40-Td CAR T cells showed improved antitumor capacity in vitro, with increased granzyme B and decreased PD-1 expression. In two xenograft and two syngeneic solid tumor mouse models, p40-Td CAR T cells showed superior efficacy in comparison to CAR T cells and attenuated side effects in comparison to CAR T cells expressing IL-18 or IL-15.
Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Oncology, Second Affiliated Hospital of Xi'an, Jiaotong
Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Oncology, Second Affiliated Hospital of Xi'an, Jiaotong University, Xi'an, China. (2) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (3) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (4) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (5) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (6) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (7) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (8) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (9) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (10) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (11) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (12) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (13) Department of Oncology, Second Affiliated Hospital of Xi'an, Jiaotong University, Xi'an, China. (14) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. gdotti@med.unc.edu. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. gdotti@med.unc.edu. (15) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. dyyang@email.unc.edu.
