Y Loriot1, A Marabelle2, J P Guégan3, F X Danlos2, B Besse4, N Chaput5, C Massard2, D Planchard1, C Robert1, C Even1, M Khettab1, L Tselikas6, L Friboulet7, F André4, I Nafia3, F Le Loarer8, J C Soria1, A Bessede3, A Italiano9. 1. Cancer Medicine Department, INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 2. Département d'Innovation Précoce et d'Essais Thérapeutiques (DITEP), INSERM U1015 & CIC1428, Université Paris Saclay, Gustave Roussy, Villejuif, France. 3. Explicyte, Bordeaux, France. 4. Cancer Medicine Department, INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France; Faculty of Medicine, University Paris-Saclay, Le Kremlin Bicêtre, 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. Interventional Radiology, Gustave Roussy, Villejuif, France. 7. Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, Villejuif, France. 8. Department of Pathology, Institut Bergonié, Bordeaux, France; Faculty of Medicine, University of Bordeaux, Bordeaux, France. 9. Département d'Innovation Précoce et d'Essais Thérapeutiques (DITEP), INSERM U1015 & CIC1428, Université Paris Saclay, Gustave Roussy, Villejuif, France; Faculty of Medicine, University of Bordeaux, Bordeaux, France; Department of Medicine, Institut Bergonié, Bordeaux, France. Electronic address: antoine.italiano@gustaveroussy.fr.
Abstract
BACKGROUND: Immune checkpoint blockers (ICBs) are now widely used in oncology. Most patients, however, do not derive benefit from these agents. Therefore, there is a crucial need to identify novel and reliable biomarkers of resistance to such treatments in order to prescribe potentially toxic and costly treatments only to patients with expected therapeutic benefits. In the wake of genomics, the study of proteins is now emerging as the new frontier for understanding real-time human biology. PATIENTS AND METHODS: We analyzed the proteome of plasma samples, collected before treatment onset, from two independent prospective cohorts of cancer patients treated with ICB (discovery cohort n = 95, validation cohort n = 292). We then investigated the correlation between protein plasma levels, clinical benefit rate, progression-free survival and overall survival by Cox proportional hazards models. RESULTS: By using an unbiased proteomics approach, we show that, in both discovery and validation cohorts, elevated baseline serum level of leukemia inhibitory factor (LIF) is associated with a poor clinical outcome in cancer patients treated with ICB, independently of other prognostic factors. We also demonstrated that the circulating level of LIF is inversely correlated with the presence of tertiary lymphoid structures in the tumor microenvironment. CONCLUSION: This novel clinical dataset brings strong evidence for the role of LIF as a potential suppressor of antitumor immunity and suggests that targeting LIF or its pathway may represent a promising approach to improve efficacy of cancer immunotherapy in combination with ICB.
BACKGROUND: Immune checkpoint blockers (ICBs) are now widely used in oncology. Most patients, however, do not derive benefit from these agents. Therefore, there is a crucial need to identify novel and reliable biomarkers of resistance to such treatments in order to prescribe potentially toxic and costly treatments only to patients with expected therapeutic benefits. In the wake of genomics, the study of proteins is now emerging as the new frontier for understanding real-time human biology. PATIENTS AND METHODS: We analyzed the proteome of plasma samples, collected before treatment onset, from two independent prospective cohorts of cancer patients treated with ICB (discovery cohort n = 95, validation cohort n = 292). We then investigated the correlation between protein plasma levels, clinical benefit rate, progression-free survival and overall survival by Cox proportional hazards models. RESULTS: By using an unbiased proteomics approach, we show that, in both discovery and validation cohorts, elevated baseline serum level of leukemia inhibitory factor (LIF) is associated with a poor clinical outcome in cancer patients treated with ICB, independently of other prognostic factors. We also demonstrated that the circulating level of LIF is inversely correlated with the presence of tertiary lymphoid structures in the tumor microenvironment. CONCLUSION: This novel clinical dataset brings strong evidence for the role of LIF as a potential suppressor of antitumor immunity and suggests that targeting LIF or its pathway may represent a promising approach to improve efficacy of cancer immunotherapy in combination with ICB.
Authors: Vladimir Semiglazov; Andrey Tseluiko; Asel Kudaybergenova; Anna Artemyeva; Petr Krivorotko; Roman Donskih Journal: Cancer Biol Med Date: 2022-06-09 Impact factor: 5.347
Authors: Mathieu Larroquette; Jean-Philippe Guegan; Benjamin Besse; Sophie Cousin; Maxime Brunet; Sylvestre Le Moulec; François Le Loarer; Christophe Rey; Jean-Charles Soria; Fabrice Barlesi; Alban Bessede; Jean-Yves Scoazec; Isabelle Soubeyran; Antoine Italiano Journal: J Immunother Cancer Date: 2022-05 Impact factor: 12.469
Authors: E Borazanci; A M Schram; E Garralda; I Brana; M Vieito Villar; A Spreafico; M Oliva; N J Lakhani; K Hoffman; R M Hallett; D Maetzel; F Hua; J Hilbert; P Giblin; J Anido; A Kelly; P J Vickers; R Wasserman; J Seoane; L L Siu; D M Hyman; D V Hoff; J Tabernero Journal: ESMO Open Date: 2022-07-31