TY - JOUR
T1 - CXCR2 inhibition enables NASH-HCC immunotherapy
AU - Leslie, Jack
AU - Mackey, John B.G.
AU - Jamieson, Thomas
AU - Ramon-Gil, Erik
AU - Drake, Thomas M.
AU - Fercoq, Frédéric
AU - Clark, William
AU - Gilroy, Kathryn
AU - Hedley, Ann
AU - Nixon, Colin
AU - Luli, Saimir
AU - Laszczewska, Maja
AU - Pinyol, Roser
AU - Esteban-Fabró, Roger
AU - Willoughby, Catherine E.
AU - Haber, Philipp K.
AU - Andreu-Oller, Carmen
AU - Rahbari, Mohammad
AU - Fan, Chaofan
AU - Pfister, Dominik
AU - Raman, Shreya
AU - Wilson, Niall
AU - Müller, Miryam
AU - Collins, Amy
AU - Geh, Daniel
AU - Fuller, Andrew
AU - McDonald, David
AU - Hulme, Gillian
AU - Filby, Andrew
AU - Cortes-Lavaud, Xabier
AU - Mohamed, Noha Ehssan
AU - Ford, Catriona A.
AU - Raffo Iraolagoitia, Ximena L.
AU - McFarlane, Amanda J.
AU - McCain, Misti V.
AU - Ridgway, Rachel A.
AU - Roberts, Edward W.
AU - Barry, Simon T.
AU - Graham, Gerard J.
AU - Heikenwälder, Mathias
AU - Reeves, Helen L.
AU - Llovet, Josep M.
AU - Carlin, Leo M.
AU - Bird, Thomas G.
AU - Sansom, Owen J.
AU - Mann, Derek A.
N1 - Funding Information:
Competing interests DM is a director of Fibrofind. JL and DM are shareholders in Fibrofind limited. SB owns shares in AstraZeneca. OJS receives funding from AstraZeneca and Novartis. TGB receives research funding support from AstraZeneca. JML receives research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha and AstraZeneca.
Funding Information:
Funding DM, OJS, HR and TB were supported by program grant funding from CRUK (C9380/A26813). DM was supported by MRC program Grants MR/K0019494/1 and MR/R023026/1. DM, OJS, HR, TB, JM and JML are supported by a CRUK programme grant (C18342/A23390). OJS is funded by a CRUK grant (CRUK A21339). LC is funded by a CRUK grant (CRUK A23983). TB receives research funding support from AstraZeneca. TB and MM were funded by the Wellcome Trust (WT107492Z). HR was funded by CRUK Newcastle Experimental Cancer Medicine Centre award (C9380/A18084). JM and TJ were supported by CRUK core funding (A17196 and A31287). JL was supported by funding from the Faculty of Medical Sciences, Newcatle University. DG is supported by the Newcastle CRUK Clinical Academic Training Programme. AC is funded by the WE Harker Foundation. RE is supported by a doctoral training grant from MICINN/MINECO (BES-2017-081286) and a mobility grant from Fundació Universitària Agustí Pedro i Pons. CEW is supported by a Sara Borrell fellowship (CD19/00109) from the Instituto de Salud Carlos III (ISCIII) and the European Social Fund. PH is supported by a fellowship grant from the German Research Foundation (DFG, HA 8754/1-1). CA-O is supported by a predoctoral research scholarship from Fulbright España. JL is supported by grants from the NIH (RO1DK56621 and RO1DK128289), the Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (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, C9380/A26813), and by the Generalitat de Catalunya (AGAUR, SGR-1358).
Publisher Copyright:
©
PY - 2022/10/1
Y1 - 2022/10/1
N2 - Objective Hepatocellular carcinoma (HCC) is increasingly associated with non-Alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. Design Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. Results Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1 + dendritic cell activation and CD8 + T cell numbers which are associated with anti-Tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8 + T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-Associated neutrophils (TANs) which switched from a protumour to anti-Tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8 + T cells in clusters that were enriched for the cytotoxic anti-Tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. Conclusion CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.
AB - Objective Hepatocellular carcinoma (HCC) is increasingly associated with non-Alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. Design Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. Results Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1 + dendritic cell activation and CD8 + T cell numbers which are associated with anti-Tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8 + T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-Associated neutrophils (TANs) which switched from a protumour to anti-Tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8 + T cells in clusters that were enriched for the cytotoxic anti-Tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. Conclusion CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.
KW - hepatocellular carcinoma
KW - immunotherapy
KW - nonalcoholic steatohepatitis
UR - http://www.scopus.com/inward/record.url?scp=85130804776&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2021-326259
DO - 10.1136/gutjnl-2021-326259
M3 - Article
C2 - 35477863
AN - SCOPUS:85130804776
SN - 0017-5749
VL - 71
SP - 2093
EP - 2106
JO - Gut
JF - Gut
IS - 10
ER -