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Supplementary Figure from Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma

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posted on 2023-03-31, 23:05 authored by Roger Esteban-Fabró, Catherine E. Willoughby, Marta Piqué-Gili, Carla Montironi, Jordi Abril-Fornaguera, Judit Peix, Laura Torrens, Agavni Mesropian, Ugne Balaseviciute, Francesc Miró-Mur, Vincenzo Mazzaferro, Roser Pinyol, Josep M. Llovet
Supplementary Figure from Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma

Funding

Ipsen Pharmaceuticals

European Social Fund

Fundació Universitària Agustí Pedro i Pons

Sara Borrell fellowship

Instituto de Salud Carlos III (ISCIII)

ESF

doctoral training

Rio Hortega fellowship

ISCIII

University of Barcelona

PERIS ICT-Suport

Departament de Salut de la Generalitat de Catalunya

FI-SDUR pre-doctoral

EILF-EASL Juan Rodés PhD Studentship

NIH

the Samuel Waxman Cancer Research Foundation

the Spanish National Health Institute

Generalitat de Catalunya

History

ARTICLE ABSTRACT

Immune checkpoint inhibitors combined with antiangiogenic agents produce benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumors received cabozantinib, anti-PD1, their combination, or placebo. Tumor and blood samples were analyzed by flow cytometry, IHC, transcriptome, and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer patient-derived xenograft model. Transcriptomic data from three human HCC cohorts (cohort 1: n = 167, cohort 2: n = 57, The Cancer Genome Atlas: n = 319) were used to cluster patients according to neutrophil features, and assess their impact on survival. The combination of cabozantinib and anti-PD1 showed increased antitumor efficacy compared with monotherapy and placebo (P < 0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced intratumor CD8+PD1+ T-cell proportions, while the combination with anti-PD1 further stimulated both effects and significantly decreased regulatory T cell (Treg) infiltration (all P < 0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P < 0.01) and memory/effector T cells (P < 0.05), while lowering the neutrophil-to-lymphocyte ratio (P < 0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumor enrichment in neutrophil features observed with the treatment combination was linked to less aggressive tumors with more differentiated and less proliferative phenotypes. Cabozantinib in combination with anti-PD1 enhanced antitumor immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favors this approach for HCC treatment.

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