Lévesque et al. found that caloric restriction mimetics (CRM) improved tumor control when combined with immunogenic cell death-inducing chemotherapy mitoxantrone (MTX); this effect was abrogated by blockade of the integrin CD11b+, which is required for myeloid cell migration. CRM or fasting before MTX uniquely increased distinct myeloid populations in tumors (fasting before MTX also expanded CD8+ T cells), and MTX treatment upregulated PD-L1 on malignant and immune cells independent of CRM combination. Triple combination of MTX or oxaliplatin with CRM and immune checkpoint blockade led to tumor regression and extended survival.
Contributed by Alex Najibi
We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8(+) T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents.
Author Info: (1) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche
Author Info: (1) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. Universite Paris-Sud/Paris XI, Faculte de Medecine, Kremlin-Bicetre, France. (2) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. Universite Paris-Sud/Paris XI, Faculte de Medecine, Kremlin-Bicetre, France. (3) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. (4) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. Universite Paris-Sud/Paris XI, Faculte de Medecine, Kremlin-Bicetre, France. (5) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. (6) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. Universite Paris-Sud/Paris XI, Faculte de Medecine, Kremlin-Bicetre, France. (7) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. Universite Paris-Sud/Paris XI, Faculte de Medecine, Kremlin-Bicetre, France. (8) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. (9) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. (10) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. (11) GenoSplice Technology, Paris, France. (12) GenoSplice Technology, Paris, France. (13) Universite Paris-Sud/Paris XI, Faculte de Medecine, Kremlin-Bicetre, France. INSERM U1015, Gustave Roussy Cancer Campus, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France. (14) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. Pole de Biologie, Hopital Europeen Georges Pompidou, AP-HP, Paris, France. Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. (15) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. INSERM U1138, Paris, France. Equipe 11 labellisee par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite de Paris, Paris, France. Sorbonne Universite, Paris, France.
