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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1512605

High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models

Provisionally accepted
Hak Su Kim Hak Su Kim 1Seung-hyun Kwon Seung-hyun Kwon 1Ok Kyung Choi Ok Kyung Choi 1Taekyu Lim Taekyu Lim 2*
  • 1 Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea
  • 2 Division of Hematology-Oncology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Republic of Korea

The final, formatted version of the article will be published soon.

    Introduction: Immune checkpoint inhibitors(ICIs) targeting programmed cell death protein 1 (PD1) confer significant survival benefits to patients with non-small cell lung cancer (NSCLC). However, there remains a substantial unmet need to identify therapeutic approaches to overcome resistance and provide benefits to these patients. High-dose ascorbic acid (AA) acts synergistically with many standard anticancer treatments. However, little is known about the effect of high-dose AA on improving the efficacy of anti-PD1 inhibitors in NSCLC. This study aimed to elucidate the effects of high-dose AA on anti-PD1 immunotherapy in NSCLC.Methods: The combined effects of high-dose AA and anti-PD1 were investigated using a coculture model of H460 cells and CD8+ T cells and an LLC1 lung cancer syngeneic mouse model. To investigate the molecular mechanism, tumor tissues from mice were analyzed by comprehensive proteomic profiling using nano-LC-ESI-MS/MS.Results: Pretreatment with a high dose of AA led to enhanced the sensitivity to the cytotoxicity of CD8+ T cells derived from healthy donor for H460 cells. Additionally, the combination of anti-PD1 and high-dose AA significantly increased CD8+ T cell cytotoxicity in H460 cells. The combination of anti-PD1 and high-dose AA showed dramatic antitumor effects in a syngeneic mouse model of lung cancer by significantly reducing tumor growth and increasing CD8+ T cell-dependent cytotoxicity and macrophage activity. Comprehensive protein analysis confirmed that high-dose AA in anti-PD1-treated tumor tissues enhanced the antitumor effects by regulating various immunerelated mechanisms, including the B cell and T cell receptor signaling pathways, Fc gamma Rmediated phagocytosis, and natural killer (NK) cell-mediated cytotoxicity. Discussion: Our results suggest that high-dose AA may be a promising adjuvant to potentiate the efficacy of anti-PD1 immunotherapy.

    Keywords: Anti-PD1, High-dose ascorbic acid, Non-small cell lung cancer, immune checkpoint inhibitors, Proteomic analysis

    Received: 17 Oct 2024; Accepted: 19 Dec 2024.

    Copyright: © 2024 Kim, Kwon, Choi and Lim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Taekyu Lim, Division of Hematology-Oncology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Republic of Korea

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.