Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma

Background and purpose Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.Basic procedures We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib—dosed orally at 5, 10 or 20 mg/kg daily—combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.Main findings Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10—a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes—in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy.Principal conclusions Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells

Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma

Background and purpose Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. Basic procedures We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. Main findings Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. Principal conclusions Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells

Biographies d’enquêtes

L’histoire de vie des personnes est un enchaînement continu d’événements de nature diverse concernant, entre autres, leur famille, leur résidence et leur profession. Pour appréhender les rythmes d’évolution multiples et imbriqués de ces différents phénomènes, il est nécessaire de disposer de données spécifiques que les enquêtes biographiques permettent de saisir au mieux dans leurs interactions. Cet ouvrage confronte, en termes directement comparables, quatorze expériences de collectes biographiques menées entre 1974 et 1997 dans divers pays du Nord (France, Pologne, Italie, Roumanie), mais aussi du Sud (en Afrique : Sénégal, Mali, Cameroun; en Amérique latine : Colombie, Mexique ; en Asie : Inde) avec des objectifs et des moyens divers. Ainsi, le cheminement théorique et les options méthodologiques qui ont présidé à chacune de ces expériences sont présentés en détail et selon un plan commun dans chaque chapitre. Ces présentations sont précédées d’une analyse comparative systématique. Ce bilan est le fruit des présentations et des discussions qui ont eu lieu lors d’un séminaire international en juin 1997, organisé par l’Ined, l’Orstom (IRD) et le Réseau Socioéconomie de l’Habitat sur « l’apport des collectes biographiques pour la connaissance de la mobilité ». Les études présentées ici apportent d’utiles éléments de réflexion aux chercheurs, enseignants et étudiants, intéressés par la collecte de données susceptibles d’améliorer la connaissance des comportements individuels, en particulier dans le domaine de la mobilité. Afin de poursuivre les travaux dans cette direction, les organisateurs ont, à l’époque, constitué le Groupe de réflexion sur l’approche biographique (Grab), animé par Éva Lelièvre, dont les activités ultérieures ont donné lieu à des rencontres régulières et à de nouvelles publications (voir http://grab.site.ined.fr)

Head and Body/Tail Pancreatic Carcinomas Are Not the Same Tumors

International audienceThe association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T samples. The 2-year overall survival (OS) was better for the head than for the B/T PDACs (44 vs. 27%, p = 0.043), especially when comparing tumors with similar TNM classification (T3/4N0M0: 67% vs. 17%, p = 0.002) or from the same molecular class (squamous subtype: 31% vs. 0%, p < 0.0001). Bailey’s molecular subtypes were differentially distributed within the two groups, with the immunogenic subtype being underrepresented in the “B/T” group (p = 0.005). Uni- and multivariate analyses indicated that PDAC anatomic location was an independent prognostic factor. Finally, the supervised analysis identified 334 genes differentially expressed. Genes upregulated in the “head” group suggested lymphocyte activation and pancreas exocrine functions. Genes upregulated in the “B/T” group were related to keratinocyte differentiation, in line with the enrichment for squamous phenotype. We identified a robust gene expression signature (GES) associated with B/T PDAC location, suggesting that head and B/T PDAC are different. This GES could serve as an indicator for differential therapeutic management based on PDAC location