To explain variable clinical response of soft-tissue sarcomas (STS) to immunotherapy, Petitprez et al. analyzed immune phenotypes of the TME from 608 STS tumors by gene expression and quantitative IHC. Five distinct immune classes were observed – immune-low (A and B) and high (D and E), and highly vascularized (C). In a phase II trial, immune-high group E had the best outcome with improved survival and response to anti-PD-1, and demonstrated increased numbers of tertiary lymphoid structures containing PD1+CD8+ T cells, follicular DCs, and high numbers of B cells. Improved survival correlated with expression of B cell-related genes and B cell number.
Contributed by Katherine Turner
ABSTRACT: Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes(1,2). The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely(3,4). To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8(+) T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.
Author Info: (1) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite,
Author Info: (1) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite, Paris, France. Centre de Recherche des Cordeliers, Sorbonne University, Paris, France. Programme Cartes d'Identite des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France. (2) Programme Cartes d'Identite des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France. (3) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. National Taiwan University Cancer Center, Taipei, Taiwan. Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan. (5) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite, Paris, France. Centre de Recherche des Cordeliers, Sorbonne University, Paris, France. (6) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Departement de Pathologie, Assistance Publique Hopitaux de Paris, Groupe Hospitalier Henri Mondor, Creteil, France. Institut Mondor de Recherche Biomedicale, Creteil, France. (7) Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan. Department of Pathology, National Taiwan University, Taipei, Taiwan. (8) Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. (9) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite, Paris, France. Centre de Recherche des Cordeliers, Sorbonne University, Paris, France. (10) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite, Paris, France. Centre de Recherche des Cordeliers, Sorbonne University, Paris, France. (11) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite, Paris, France. Centre de Recherche des Cordeliers, Sorbonne University, Paris, France. (12) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite, Paris, France. Centre de Recherche des Cordeliers, Sorbonne University, Paris, France. (13) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite, Paris, France. Centre de Recherche des Cordeliers, Sorbonne University, Paris, France. (14) Department of Biology and Pathology, Gustave Roussy, Villejuif, France. (15) Institut Bergonie, Bordeaux, France. Bioinformatics Unit, Institut Bergonie, Bordeaux, France. (16) Institut Bergonie, Bordeaux, France. Bioinformatics Unit, Institut Bergonie, Bordeaux, France. (17) Institut Bergonie, Bordeaux, France. Department of Medical Oncology, Institut Bergonie, Bordeaux, France. (18) Department of Medicine, Divison of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (19) Cancer Research and Biostatistics, Seattle, WA, USA. (20) Sarcoma Alliance for Research Through Collaboration, Ann Arbor, MI, USA. (21) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Institut Bergonie, Bordeaux, France. Department of Medical Oncology, Institut Bergonie, Bordeaux, France. University of Bordeaux, Bordeaux, France. (27) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite, Paris, France. Centre de Recherche des Cordeliers, Sorbonne University, Paris, France. (28) Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. htawbi@mdanderson.org. (29) Team Cancer, Immune Control and Escape, Centre de Recherche des Cordeliers, INSERM, Paris, France. herve.fridman@crc.jussieu.fr. Centre de Recherche des Cordeliers, Universite de Paris, Sorbonne Paris Cite, Paris, France. herve.fridman@crc.jussieu.fr. Centre de Recherche des Cordeliers, Sorbonne University, Paris, France. herve.fridman@crc.jussieu.fr.
