TY - JOUR
T1 - Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma
AU - Esteban-Fabró, Roger
AU - Willoughby, Catherine E.
AU - Piqué-Gili, Marta
AU - Montironi, Carla
AU - Abril-Fornaguera, Jordi
AU - Peix, Judit
AU - Torrens, Laura
AU - Mesropian, Agavni
AU - Balaseviciute, Ugne
AU - Miró-Mur, Francesc
AU - Mazzaferro, Vincenzo
AU - Pinyol, Roser
AU - Llovet, Josep M.
N1 - Funding Information:
J.M. Llovet reports grants and personal fees from Bayer HealthCare Pharmaceuticals, Eisai Inc, and Ipsen; grants from Boehringer Ingelheim; and personal fees from Eli Lilly, Merck, Bristol Myers Squibb, Glycotest, Nucleix, Genentech, Roche, AstraZeneca, Omega Therapeutics, Iylon, Mina Alpha, and Boston Scientific outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
This study was sponsored by Ipsen Pharmaceuticals. R. Esteban-Fabró is supported by a doctoral training grant (BES-2017-081286) from MCIN/AEI/ 10.13039/501100011033 and the European Social Fund (ESF) and a mobility grant from Fundació Universitària Agustí Pedro i Pons. C.E. Willoughby is supported by a Sara Borrell fellowship (CD19/00109) from the Instituto de Salud Carlos III (ISCIII) and ESF. M. Piqué-Gili is supported by a doctoral training grant (PRE2020-094716) from MCIN/AEI/10.13039/501100011033 and ESF, and a mobility grant from Fundació Universitària Agustí Pedro i Pons. C. Montironi is supported by a Rio Hortega fellowship (CM19/00039) from ISCIII and ESF. J. Abril-Fornaguera is supported by a doctoral training grant from the University of Barcelona (PREDOCS-UB 2020) and a mobility grant from Fundació Uni-versitària Agustí Pedro i Pons. J. Peix is supported by a PERIS ICT-Suport grant from the Departament de Salut de la Generalitat de Catalunya (SLT017/20/ 000206). A. Mesropian is supported by a FI-SDUR pre-doctoral support grant (BDNS 550325) from the Agency for Management of University and Research Grants (AGAUR) and the Generalitat de Catalunya. U. Balaseviciute is supported by an EILF-EASL Juan Rodés PhD Studentship (EASL_JR_12_20) from the European Association for the Study of the Liver (EASL) and the EASL International Liver Foundation (EILF). J.M. Llovet is supported by grants from the European Commission (EC) Horizon 2020 Program (HEPCAR, proposal number 667273-2), the NIH (RO1DK56621 and RO1DK128289), the Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (MICINN, SAF-2016-76390 and PID2019-105378RB-I00), through an Accelerator award in partnership between Cancer Research UK, Fondazione AIRC and Fundación Científica de la Asociación Española Contra el Cáncer (HUNTER, ref. C9380/ A26813), and by the Generalitat de Catalunya (AGAUR, SGR-1358). We are indebted to the Cytometry and Cell Sorting Core Facility of the Institut d’Inves-tigacions Biomèdiques August Pi i Sunyer (IDIBAPS), particularly Dr. Isabel Crespo, for excellent flow cytometry technical assistance.
Publisher Copyright:
©2022 American Association for Cancer Research
PY - 2022/6/1
Y1 - 2022/6/1
N2 - Purpose: 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. Experimental Design: 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 ¼ 167, cohort 2: n ¼ 57, The Cancer Genome Atlas: n ¼ 319) were used to cluster patients according to neutrophil features, and assess their impact on survival. Results: 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 CD8þPD1þ 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. Conclusions: 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.
AB - Purpose: 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. Experimental Design: 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 ¼ 167, cohort 2: n ¼ 57, The Cancer Genome Atlas: n ¼ 319) were used to cluster patients according to neutrophil features, and assess their impact on survival. Results: 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 CD8þPD1þ 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. Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=85131221681&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-2517
DO - 10.1158/1078-0432.CCR-21-2517
M3 - Article
C2 - 35302601
AN - SCOPUS:85131221681
SN - 1078-0432
VL - 28
SP - 2449
EP - 2460
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -