APR-246 increases tumor antigenicity independent of p53

Judith Michels; Divya Venkatesh; Cailian Liu; Sadna Budhu; Hong Zhong; Mariam M George; Daniel Thach; Zhong-Ke Yao; Ouathek Ouerfelli; Hengrui Liu; Brent R Stockwell; Luis Felipe Campesato; Dmitriy Zamarin; Roberta Zappasodi; Jedd D Wolchok; Taha Merghoub

doi:10.26508/lsa.202301999

APR-246 increases tumor antigenicity independent of p53

Life Sci Alliance. 2023 Oct 27;7(1):e202301999. doi: 10.26508/lsa.202301999. Print 2024 Jan.

Authors

Judith Michels^{1

2}, Divya Venkatesh^{1

2}, Cailian Liu^{1

2}, Sadna Budhu^{1

2}, Hong Zhong^{1

2}, Mariam M George^{1

2}, Daniel Thach^{1

2}, Zhong-Ke Yao³, Ouathek Ouerfelli³, Hengrui Liu⁴, Brent R Stockwell^{4

5}, Luis Felipe Campesato^{1

2}, Dmitriy Zamarin^{6

7

8}, Roberta Zappasodi⁹, Jedd D Wolchok^{10

2

9}, Taha Merghoub^{11

2

9}

Affiliations

¹ Department of Pharmacology, Swim Across America and Ludwig Collaborative Laboratory, Weill Cornell Medicine, New York, NY, USA.
² Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
³ The Organic Synthesis Core Facility, MSK, New York, NY, USA.
⁴ Department of Biological Sciences, Columbia University, New York, NY, USA.
⁵ Department of Chemistry, Columbia University, New York, NY, USA.
⁶ Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷ Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹ Department of Medicine, Weill Cornell, New York, NY, USA.
¹⁰ Department of Pharmacology, Swim Across America and Ludwig Collaborative Laboratory, Weill Cornell Medicine, New York, NY, USA [email protected].
¹¹ Department of Pharmacology, Swim Across America and Ludwig Collaborative Laboratory, Weill Cornell Medicine, New York, NY, USA [email protected].

Abstract

We previously reported that activation of p53 by APR-246 reprograms tumor-associated macrophages to overcome immune checkpoint blockade resistance. Here, we demonstrate that APR-246 and its active moiety, methylene quinuclidinone (MQ) can enhance the immunogenicity of tumor cells directly. MQ treatment of murine B16F10 melanoma cells promoted activation of melanoma-specific CD8⁺ T cells and increased the efficacy of a tumor cell vaccine using MQ-treated cells even when the B16F10 cells lacked p53. We then designed a novel combination of APR-246 with the TLR-4 agonist, monophosphoryl lipid A, and a CD40 agonist to further enhance these immunogenic effects and demonstrated a significant antitumor response. We propose that the immunogenic effect of MQ can be linked to its thiol-reactive alkylating ability as we observed similar immunogenic effects with the broad-spectrum cysteine-reactive compound, iodoacetamide. Our results thus indicate that combination of APR-246 with immunomodulatory agents may elicit effective antitumor immune response irrespective of the tumor's p53 mutation status.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm
CD8-Positive T-Lymphocytes*
Melanoma*
Mice
Tumor Suppressor Protein p53 / genetics

Substances

Tumor Suppressor Protein p53
Antigens, Neoplasm

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States