A Bessede1, A Marabelle2, J P Guégan1, F X Danlos2, S Cousin3, F Peyraud4, N Chaput5, M Spalato3, G Roubaud3, M Cabart3, M Khettab6, A Chaibi1, C Rey1, I Nafia1, F X Mahon7, J C Soria8, A Italiano9. 1. Explicyte, Bordeaux, France. 2. Département d'Innovation Précoce et d'Essais Thérapeutiques (DITEP), INSERM U1015 & CIC1428, Université Paris-Saclay, Gustave Roussy, Villejuif, France. 3. Department of Medicine, Institut Bergonié, Bordeaux, France. 4. Explicyte, Bordeaux, France; Département d'Innovation Précoce et d'Essais Thérapeutiques (DITEP), INSERM U1015 & CIC1428, Université Paris-Saclay, Gustave Roussy, Villejuif, France. 5. Laboratory of Immunomonitoring in Oncology, Gustave Roussy Cancer Campus, CNRS-UMS 3655 and INSERM-US23, Villejuif, France; Faculty of Pharmacy, University Paris-Saclay, Chatenay-Malabry, France; Laboratory of Genetic Instability and Oncogenesis, UMR CNRS 8200, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 6. Faculty of Medicine, University of Bordeaux, Bordeaux, France. 7. Department of Medicine, Institut Bergonié, Bordeaux, France; Faculty of Medicine, University of Bordeaux, Bordeaux, France. 8. Department of Medicine, Gustave Roussy, Villejuif, France. 9. Département d'Innovation Précoce et d'Essais Thérapeutiques (DITEP), INSERM U1015 & CIC1428, Université Paris-Saclay, Gustave Roussy, Villejuif, France; Department of Medicine, Institut Bergonié, Bordeaux, France; Faculty of Medicine, University of Bordeaux, Bordeaux, France. Electronic address: antoine.italiano@gustaveroussy.fr.
Abstract
BACKGROUND: Acetaminophen (APAP) use has been associated with blunted vaccine immune responses. This study aimed to assess APAP impact on immunotherapy efficacy in patients with cancer. PATIENTS AND METHODS: Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICBs). The immunomodulatory effects of APAP were evaluated on a preclinical tumor model and on human peripheral blood mononuclear cells (PBMCs) from healthy donors. RESULTS: Detectable plasma APAP levels at treatment onset were associated with a significantly worse clinical outcome in ICB-treated cancer patients, independently of other prognostic factors. APAP significantly reduced ICB efficacy in the preclinical MC38 model, as well as the production of PD-1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly up-regulated upon treatment with ICB in cancer patients taking APAP. CONCLUSIONS: This study provides strong preclinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.
BACKGROUND: Acetaminophen (APAP) use has been associated with blunted vaccine immune responses. This study aimed to assess APAP impact on immunotherapy efficacy in patients with cancer. PATIENTS AND METHODS: Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICBs). The immunomodulatory effects of APAP were evaluated on a preclinical tumor model and on human peripheral blood mononuclear cells (PBMCs) from healthy donors. RESULTS: Detectable plasma APAP levels at treatment onset were associated with a significantly worse clinical outcome in ICB-treated cancer patients, independently of other prognostic factors. APAP significantly reduced ICB efficacy in the preclinical MC38 model, as well as the production of PD-1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly up-regulated upon treatment with ICB in cancer patients taking APAP. CONCLUSIONS: This study provides strong preclinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.