Spatial distribution of tumour immune infiltrate predicts outcomes of patients with high-risk soft tissue sarcomas after neoadjuvant chemotherapyResearch in context
Sandro Pasquali,
Viviana Vallacchi,
Luca Lalli,
Paola Collini,
Marta Barisella,
Cleofe Romagosa,
Silvia Bague,
Jean Michel Coindre,
Angelo Paolo Dei Tos,
Emanuela Palmerini,
Vittorio Quagliuolo,
Javier Martin-Broto,
Antonio Lopez-Pousa,
Giovanni Grignani,
Jean-Yves Blay,
Robert Diaz Beveridge,
Elena Casiraghi,
Silvia Brich,
Salvatore Lorenzo Renne,
Laura Bergamaschi,
Barbara Vergani,
Marta Sbaraglia,
Paolo Giovanni Casali,
Licia Rivoltini,
Silvia Stacchiotti,
Alessandro Gronchi
Affiliations
Sandro Pasquali
Molecular Pharmacology, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy; Corresponding author. Molecular Pharmacology, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G Amadeo 42, 20133, Milano, Italy.
Viviana Vallacchi
Translational Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
Luca Lalli
Translational Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy; Corresponding author. Translational Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G Venezian 1, 20133, Milano, Italy.
Paola Collini
Soft Tissue Tumor Pathology Unit, Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
Marta Barisella
Pathology Unit, ASST Fatebenefratelli Sacco, Milan, Italy
Cleofe Romagosa
Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain
Silvia Bague
Pathology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Jean Michel Coindre
Department of Pathology, Institut Bergonié, 33000, Bordeaux, France; INSERM U1218 ACTION, Institut Bergonié, 33000, Bordeaux, France
Angelo Paolo Dei Tos
Surgical Pathology & Cytopathology Unit, Department of Medicine - DIMED, University of Padua, Padua, Italy
Emanuela Palmerini
Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Vittorio Quagliuolo
Surgery Department, IRCCS Humanitas Research Hospital, Rozzano, Italy
Javier Martin-Broto
Oncology Department, Fundación Jiménez Díaz University Hospital, Madrid, Spain
Antonio Lopez-Pousa
Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí, 89, 08041, Barcelona, Spain
Giovanni Grignani
Medical Oncology Unit, Città della Salute e della Scienza Hospital, Turin, Italy
Jean-Yves Blay
Centre Léon Bérard & Université Claude Bernard Lyon 1, Lyon, France
Robert Diaz Beveridge
Department of Cancer Medicine, Hospital Universitari i Politècnic La Fe, Valencia, Spain
Elena Casiraghi
AnacletoLab, Department of Computer Science “Giovanni degli Antoni”, Università degli Studi di Milano, Milan, Italy
Silvia Brich
Soft Tissue Tumor Pathology Unit, Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
Salvatore Lorenzo Renne
Pathology Department, IRCCS Humanitas Research Hospital, Rozzano, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
Laura Bergamaschi
Translational Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
Barbara Vergani
School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy
Marta Sbaraglia
Surgical Pathology & Cytopathology Unit, Department of Medicine - DIMED, University of Padua, Padua, Italy
Paolo Giovanni Casali
Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
Licia Rivoltini
Translational Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy; Corresponding author. Translational Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G Venezian 1, 20133, Milano, Italy.
Silvia Stacchiotti
Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
Alessandro Gronchi
Sarcoma Service, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy; Corresponding author. Sarcoma Service, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G Venezian 1, 20133, Milano, Italy.
Summary: Background: Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis. Methods: The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS). Findings: Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI. Interpretation: The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS. Funding: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds—2016, Italian Ministry of Health; AIRC Grant [ID#28546].
