Markowitz et al. studied metabolic mechanisms regulating TCF1high progenitor CD8+ T cells, which are critical for immunotherapy efficacy. By comparing metabolic pathway genes in tumors that respond differentially to PD-1-targeted therapies, they found that knockdown of glycolytic pyruvate kinase muscle 2 (PKM2) in CD8+ T cells resulted in decreased glycolytic flux, increased pentose phosphate pathway (PPP) activity, and enrichment of a TCF1high progenitor exhausted-like phenotype with increased responsiveness to PD-1 blockade in vivo. A small molecule PPP agonist phenocopied the effects of PKM2 KO, and enhanced the efficacy of T cells in a patient-derived human organoid system.
Contributed by Katherine Turner
ABSTRACT: TCF1(high) progenitor CD8(+) T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1(high) progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2(KO) CD8(+) T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-(13)C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8(+) T cells toward a TCF1(high) population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8(+) T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.
Author Info: (1) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Department of C
Author Info: (1) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. (2) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. (3) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Regeneron Pharmaceuticals, Tarrytown, NY, USA. (4) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. (5) HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. Gritstone Bio, Boston, MA, USA. (6) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. (7) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. (8) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. SalioGen Therapeutics, Lexington, MA, USA. (9) Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA. (10) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (11) Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. Altos Labs, Redwood City, CA, USA. (12) HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (13) Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA. Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, NY, USA. (14) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA. (15) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (16) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu. Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu. Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. vim2010@med.cornell.edu.
