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Master Thesis

Métabolites circulants de la voie du tryptophane et réponse à l'immunothérapie chez les patients atteints de cancer : valeur prédictive et mécanisme de résistance

Abstract : Introduction: despite remarkable success of immune checkpoint inhibitors (ICIs) targeting anti- programmed cell death protein 1 (anti-PD-1) or its ligand (PD-L1), only a minority of cancer patients derive long-term clinical benefit from these agents. Therefore, there is a crucial need to identify novel and reliable biomarkers of response or resistance to such treatments in order to select patients who are more likely to benefit. Given the known role of the indoleamine-2,3 dioxygenase (IDO1) in modulating antitumor immunity, we aimed to evaluate the circulating IDO1-associated metabolites, namely the kynurenine (Kyn) and tryptophan (Trp), as a possible biomarker of response to ICIs in patients with solid tumors. Methods: we analyzed the levels of circulating Kyn, Trp and Kyn/Trp ratio of plasma samples, collected before onset and on-therapy and measured by enzyme-linked immunosorbent assay (ELISA), from two independent prospective cohorts of cancer patients treated with ICI (Discovery cohort, n=100; Validation cohort, n=292). We then investigated the correlation between these metabolites (Kyn, Trp and Kyn/Trp ratio), clinical benefit rate (durable clinical benefit versus non- durable benefit), progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards models. Results: in both Discovery and Validation cohorts, we found that elevated baseline level or Trp is associated with durable clinical benefit and better clinical outcome in cancer patients treated with ICI. We observed that circulating level of Trp inversely correlates with PD-L1 tumor expression. By subgroup analysis, we also showed that high circulating level is associated with prolonged survival in both PD-L1 negative and low CD8 T-cell density within tumors. In the Validation cohort, we also demonstrated that decrease of Trp level among patients receiving ICI correlates with worse clinical outcome and shorter survival, suggesting a possible mechanism of primary resistance. Conclusion: these novel clinical findings bring strong evidence for the role of circulating Trp as a potential biomarker of response to ICI and suggest that targeting Trp catabolic pathway, such as IDO1, may represent a promising approach to improve efficacy of cancer immunotherapy in combination with ICI.
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https://dumas.ccsd.cnrs.fr/dumas-03352840
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Submitted on : Thursday, September 23, 2021 - 3:26:05 PM
Last modification on : Saturday, October 23, 2021 - 3:24:39 AM

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  • HAL Id : dumas-03352840, version 1

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Florent Peyraud. Métabolites circulants de la voie du tryptophane et réponse à l'immunothérapie chez les patients atteints de cancer : valeur prédictive et mécanisme de résistance. Sciences du Vivant [q-bio]. 2021. ⟨dumas-03352840⟩

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