Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade

Research ArticleOncologyTherapeutics Open Access | 10.1172/JCI148141

Arnab Ghosh,1,2,3 Judith Michels,1,2 Riccardo Mezzadra,4 Divya Venkatesh,1,2 Lauren Dong,1,2 Ricardo Gomez,1,2 Fadi Samaan,1,2 Yu-Jui Ho,4 Luis Felipe Campesato,1,2 Levi Mangarin,1,2 John Fak,5 Nathan Suek,1,2 Aliya Holland,1,2 Cailian Liu,1,2 Mohsen Abu-Akeel,1,2 Yonina Bykov,1,2 Hong Zhong,1,2 Kelly Fitzgerald,1,2 Sadna Budhu,1,2 Andrew Chow,1,2,3 Roberta Zappasodi,1,2 Katherine S. Panageas,6 Olivier de Henau,1,2 Marcus Ruscetti,4 Scott W. Lowe,4,7 Taha Merghoub,1,2,3 and Jedd D. Wolchok1,2,3

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Ghosh, A. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Michels, J. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Mezzadra, R. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Venkatesh, D. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Dong, L. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Gomez, R. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Samaan, F. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Ho, Y. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Campesato, L. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Mangarin, L. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Fak, J. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Suek, N. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Holland, A. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Liu, C. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Abu-Akeel, M. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Bykov, Y. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Zhong, H. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Fitzgerald, K. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Budhu, S. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Chow, A. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Zappasodi, R. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Panageas, K. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by de Henau, O. in: JCI | PubMed | Google Scholar

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Ruscetti, M. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Lowe, S. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Merghoub, T. in: JCI | PubMed | Google Scholar |

1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy,

2Immuno-Oncology Service, Human Oncology and Pathogenesis Program,

3Department of Medicine, and

4Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

5Rockefeller University, New York, New York, USA.

6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

7Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Address correspondence to: Jedd D. Wolchok, 1275 York Avenue, New York, New York 10065, USA. Phone: 646.888.2315; Email: wolchokj@mskcc.org. RZ’s present address is: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. MR’s present address is: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Authorship note: AG and JM are co–first authors.

Find articles by Wolchok, J. in: JCI | PubMed | Google Scholar |

Authorship note: AG and JM are co–first authors.

Published September 15, 2022 - More info

Published in Volume 132, Issue 18 on September 15, 2022
J Clin Invest. 2022;132(18):e148141. https://doi.org/10.1172/JCI148141.
© 2022 Ghosh et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published September 15, 2022 - Version history
Received: January 29, 2021; Accepted: July 21, 2022 View PDF Abstract

In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule–based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.

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