Paper
High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model
Published Jan 7, 2020 · Rebecca A. Luchtel, T. Bhagat, K. Pradhan
Proceedings of the National Academy of Sciences of the United States of America
114
Citations
4
Influential Citations
Abstract
Significance New strategies are needed to improve efficacy of anti-PD1 therapy in cancer treatment. Ascorbic acid (AA, vitamin C) has been previously shown to cause genome-wide demethylation in multiple malignancies by enhancing the activity of the Ten-Eleven Translocation (TET) enzymes. This study shows that AA treatment 1) increases immunogenicity of lymphoma cells; 2) enhances intratumoral infiltration of CD8+ T cells and macrophages; and 3) synergizes with anti-PD1 checkpoint inhibition in a syngeneic lymphoma mouse model via marked activation of cytotoxic cells (cytotoxic T cells and NK cells) and antigen presenting cells. The data provide a compelling rationale for testing combinations of high-dose AA and anti-PD1 agents in patients with aggressive B cell lymphoma and in preclinical models of other malignancies. Major efforts are underway to identify agents that can potentiate effects of immune checkpoint inhibition. Here, we show that ascorbic acid (AA) treatment caused genomewide demethylation and enhanced expression of endogenous retroviral elements in lymphoma cells. AA also increased 5-hydroxymethylcytosine (5hmC) levels of CD8+ T cells and enhanced their cytotoxic activity in a lymphoma coculture system. High-dose AA treatment synergized with anti-PD1 therapy in a syngeneic lymphoma mouse model, resulting in marked inhibition of tumor growth compared with either agent alone. Analysis of the intratumoral epigenome revealed increased 5hmC with AA treatment, consistent with in vitro findings. Analysis of the tumor immune microenvironment revealed that AA strikingly increased intratumoral infiltration of CD8+ T cells and macrophages, suggesting enhanced tumor immune recognition. The combination treatment markedly enhanced intratumoral infiltration of macrophages and CD8+ T lymphocytes, granzyme B production by cytotoxic cells (cytotoxic T cells and natural killer cells), and interleukin 12 production by antigen-presenting cells compared with single-agent anti-PD1. These data indicate that AA potentiates anti-PD1 checkpoint inhibition through synergistic mechanisms. The study provides compelling rationale for testing combinations of high-dose AA and anti-PD1 agents in patients with aggressive B cell lymphoma as well as in preclinical models of other malignancies.
Non-RCT
Animal Study
Highly CitedHigh-dose ascorbic acid combined with anti-PD1 therapy effectively inhibits tumor growth in a lymphoma mouse model, suggesting potential for improved cancer treatment.
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