Published March 19, 2024
| Version v1
Journal article
Unveiling CXCR2 as a promising therapeutic target in renal cell carcinoma: exploring the immunotherapeutic paradigm shift through its inhibition by RCT001
Creators
- Montemagno, Christopher
- Jacquel, Arnaud
- Pandiani, Charlotte
- Rastoin, Olivia
- Dawaliby, Rosie
- Schmitt, Thomas
- Bourgoin, Maxence
- Palenzuela, Héliciane
- Rossi, Anne-Laure
- Ambrosetti, Damien
- Durivault, Jérôme
- Luciano, Frédéric
- Borchiellini, Delphine
- Le Du, Julie
- Gonçalves, Leticia Christina Pires
- Auberger, Patrick
- Benhida, Rachid
- Kinget, Lisa
- Beuselinck, Benoit
- Ronco, Cyril
- Pagès, Gilles
- Dufies, Maeva
Contributors
Others:
- Centre Scientifique de Monaco (CSM)
- Centre méditerranéen de médecine moléculaire (C3M) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UniCA)
- Institut de Recherche sur le Cancer et le Vieillissement (IRCAN) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UniCA)
- Chercheur indépendant
- Centre Hospitalier Universitaire de Nice (CHU Nice)
- Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL) ; UNICANCER-Université Côte d'Azur (UniCA)
- Institut de Chimie de Nice (ICN) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UniCA)
- University Hospitals Leuven [Leuven]
- Catholic University of Leuven = Katholieke Universiteit Leuven (KU Leuven)
- Institut universitaire de France (IUF) ; Ministère de l'Education nationale, de l'Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)
- This work was supported by the A.R.Tu.R foundation (https://artur-rein.org), by Canceropole PACA (EMA founding), by the national research agency (agence nationale de la recherche, ANR, AAPG 2023), the Government of the Principality of Monaco, the Fondation François-Xavier Mora, the Fondation de France.
Description
BackgroundIn clear cell renal cell carcinoma (ccRCC), first-line treatment combines nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4), yielding long-term remissions but with only a 40% success rate. Our study explored the potential of enhancing ccRCC treatment by concurrently using CXCR2 inhibitors alongside immunotherapies.MethodsWe analyzed ELR + CXCL levels and their correlation with patient survival during immunotherapy. RCT001, a unique CXCR2 inhibitor, was examined for its mechanism of action, particularly its effects on human primary macrophages. We tested the synergistic impact of RCT001 in combination with immunotherapies in both mouse models of ccRCC and human ccRCC in the presence of human PBMC.ResultsElevated ELR + CXCL cytokine levels were found to correlate with reduced overall survival during immunotherapy. RCT001, our optimized compound, acted as an inverse agonist, effectively inhibiting angiogenesis and reducing viability of primary ccRCC cells. It redirected M2-like macrophages without affecting M1-like macrophage polarization directed against the tumor. In mouse models, RCT001 enhanced the efficacy of anti-CTLA4 + anti-PD1 by inhibiting tumor-associated M2 macrophages and tumor-associated neutrophils. It also impacted the activation of CD4 T lymphocytes, reducing immune-tolerant lymphocytes while increasing activated natural killer and dendritic cells. Similar effectiveness was observed in human RCC tumors when RCT001 was combined with anti-PD-1 treatment.ConclusionsRCT001, by inhibiting CXCR2 through its unique mechanism, effectively suppresses ccRCC cell proliferation, angiogenesis, and M2 macrophage polarization. This optimization potentiates the efficacy of immunotherapy and holds promise for significantly improving the survival prospects of metastatic ccRCC patients.
Abstract
International audienceAdditional details
Identifiers
- URL
- https://hal.science/hal-04571570
- URN
- urn:oai:HAL:hal-04571570v1
Origin repository
- Origin repository
- UNICA