LBPO.CL02 · 临床研究 · Late-Breaking

Spatial immune architecture at single-cell resolution predicts response to atezolizumab plus bevacizumab in advanced HCC

编号 LB123 展板 10 时间 4/20 09:00–12:00 区域 Section 52 主讲 Anna Vila-Escoda, PhD

分会场 Late-Breaking Research: Clinical Research 2

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作者与单位

Anna Vila-Escoda¹, Marta Piqué-Gili¹, Marta Casado-Pelaez², Roser Pinyol³, Ana Hernández de Sande³, Verónica Davalos², Albert Gris-Oliver³, Carla Montironi⁴, Judit Peix³, Daniela Grases⁵, Ezequiel Mauro⁶, Guillem Cano-Segarra³, Sarah Cappuyns⁷, Igor Figueiredo⁸, Giorgio Ioannou⁸, Edgar Gonzalez-Kozlova⁸, Tim Meyer⁹, Anja Lachenmayer¹⁰, Jens U Marquardt¹¹, Helen L Reeves¹², Julien Edeline¹³, Fabian Finkelmeier¹⁴, Jörg Trojan¹⁴, Sacha Gnjatic⁸, Jean-Frederic Blanc¹⁵, Richard A Hubner¹⁶, Matthias Pinter¹⁷, Tom Luedde¹⁸, Arndt Vogel¹⁹, Daniela Sia²⁰, Vincenzo Mazzaferro²¹, Manel Esteller²², Jeroen Dekervel²³, Eduard Porta-Pardo²⁴, Josep M Llovet¹

¹Liver Cancer Translational Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona. Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY,²Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), IJC Building, Germans Trias I Pujol, Barcelona, Spain,³Liver Cancer Translational Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona, Spain,⁴Liver Cancer Translational Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic; Pathology Department and Molecular Biology Core, Hospital Clínic of Barcelona, Barcelona, Spain,⁵Josep Carreras Leukemia Research Institute (IJC), Barcelona, Spain,⁶Liver Cancer Translational Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Barcelona, Spain,⁷Digestive Oncology, Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium,⁸Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY,⁹Research Department of Oncology, UCL Cancer Institute, University College London, Royal Free Hospital, London, United Kingdom,¹⁰Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland,¹¹Department of Medicine I, University Medical Center Schleswig Holstein Campus Lübeck, Lübeck, Germany,¹²Newcastle University Translational Research Institute, Newcastle upon Tyne NHS Foundation Trust, and NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom,¹³Department of Medical Oncology, Centre Eugène Marquis, Rennes, France,¹⁴Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany,¹⁵Department of Hepatogastroenterology and Medical Oncology, CHU de Bordeaux Hôpital Haut-Lévêque, Pessac, France,¹⁶Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, United Kingdom,¹⁷Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Vienna, Vienna, Austria,¹⁸Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Dusseldorf, Medical Faculty at Heinrich Heine University Dusseldorf, Dusseldorf, Germany,¹⁹Hannover Medical School, Hannover, Austria,²⁰Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY,²¹Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy,²²Josep Carreras Leukemia Research Institute (IJC).Centro de Investigacion Biomedica en Red Cancer. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain,²³Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium,²⁴Josep Carreras Leukemia Research Institute (IJC). Barcelona Supercomputing Center (BSC), Barcelona, Spain

摘要 Abstract

Background: Atezolizumab+bevacizumab (atezo+bev) is a first-line therapy for advanced hepatocellular carcinoma (aHCC) with ~30% objective responses. Single-cell studies identified responses linked to CD8⁺ T effector cells (CD8_Tex and Temra) and CXCL10⁺ macrophages (Macro_CXCL10), and resistance to TREM2⁺ macrophages (Macro_TREM2) and CD14⁺ monocytes (Mono_CD14). We hypothesized that, beyond cell composition, immune spatial organization within the tumor microenvironment (TME) determines response to atezo+bev. Methods: Single-cell spatial transcriptomics (ST) was performed on 27 aHCCs (9 atezo+bev responders and 18 resistant) using the Xenium Prime 5.000-gene panel (10x Genomics) customized with 100 additional genes. For local tissue organization, distances between cells were computed using the dbscan package [radius(r)=300µm]. Immune cell clusters were defined as groups of ≥3 immune cells within 100 µm, and were identified through a density-based algorithm. This spatial clustering was assessed using both ST and multiplexed immunohistochemistry (mIHC) data. Cell-to-cell interactions (neighborhoods) were analyzed (r=25µm). Ligand-receptor interactions were evaluated using a spatial neighborhood-based approach. Results: ST of 27 aHCCs yielded 4.6 million cells. In responders, CD8_Tex and Temra, and Macro_CXCL10 cells localized within the tumor and were closer to cancer cells ( p=0.02 , p=0.08 , and p=0.1 , respectively). Furthermore, in responders, tumor hepatocytes exhibited a significantly enriched lymphoid neighborhood composition and significantly higher rates of immune-recruting interactions, including PDL1-PD1, CXCL9-CXCR3 and CXCL10-CXCR3 (p<0.05). Non-responders were enriched in TREM2⁺ macrophage-containing clusters. Specifically, they showed Macro_TREM2-pure clusters (10% vs 0%, p=0.009), mixed Macro_TREM2-Mono_CD14 clusters (27% vs 5%, p=0.03), and mixed Macro_TREM2-CD8⁺ T-cell clusters (38% vs 22%, p=0.04). This was accompanied by enrichment of the CXCL12-CXCR4 chemokine axis, consistent with an immunosuppressive TME. Using mIHC, we confirmed enrichment of Macro_TREM2-pure (p=0.02) and Macro_TREM2-CD8⁺ mixed clusters (p=0.03). Conclusions: Atezo+bev response in HCC is marked by intratumoral effector CD8⁺ T cells and CXCL10_Macro, tumor hepatocytes enriched in lymphoid neighborhoods, and immune-recruiting ligand-receptor interactions, whereas resistance is driven by TREM2_Macro clusters and CXCL12-CXCR4 signaling. These findings identify spatial immune organization as a key determinant of response to atezo+bev.

利益披露 Disclosure

A. Vila-Escoda, None.. M. Piqué-Gili, None.. M. Casado-Pelaez, None.. R. Pinyol, None.. A. Hernández de Sande, None.. V. Davalos, None.. A. Gris-Oliver, None.. C. Montironi, None.. J. Peix, None.. D. Grases, None.. E. Mauro, None.. G. Cano-Segarra, None.. S. Cappuyns, None.. I. Figueiredo, None.. G. Ioannou, None.. E. Gonzalez-Kozlova, None.. T. Meyer, None.. A. Lachenmayer, None.. J. Marquardt, None.. H. Reeves, None.. J. Edeline, None.. F. Finkelmeier, None.. J. Trojan, None.. S. Gnjatic, None.. J. Blanc, None.. R. Hubner, None. M. Pinter, AstraZeneca Other, speaker honoraria consultant/advisory board member. Bayer Other, speaker honoraria consultant/advisory board member. BMS Other, speaker honoraria consultant/advisory board member. Eisai Other, speaker honoraria consultant/advisory board member. Ipsen Other, speaker honoraria consultant/advisory board member. Lilly Other, speaker honoraria consultant/advisory board member. MSD Other, speaker honoraria consultant/advisory board member. Roche speaker honoraria consultant/advisory board member. T. Luedde, None.. A. Vogel, None.. D. Sia, None.. V. Mazzaferro, None.. M. Esteller, None.. J. Dekervel, None.. E. Porta-Pardo, None. J. Llovet, Genentech Other, Consultancy/Sponsored Lectures. Roche Other, Consultancy / Sponsored Lectures. Eisai inc Other, Consultancy / Sponsored Lectures. Merck Other, Consultancy / Sponsored Lectures. Astrazeneca Other, Consultancy / Sponsored Lectures. Bayer Pharmaceuticals Other, Consultancy / Sponsored Lectures. Abbvie Other, Consultancy / Sponsored Lectures. Sanofi Other, Consultancy / Sponsored Lectures. Moderna Other, Consultancy / Sponsored Lectures. Glycotest Other, Consultancy / Sponsored Lectures. Exelixis Other, Consultancy / Sponsored Lectures. Boehringer Ingelheim Other, Consultancy / Sponsored Lectures. Brystol Myers Squibb Other, Data Safety Monitoring Board for Industry or commercial enterprise.

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