Immune classification of soft tissue sarcoma and its association with molecular characteristics, and clinical outcome

Background: Soft tissue sarcomas (STS) form a group of rare cancers which accounts for around 1% of tumors. In the era of immunotherapy, little is known on the clinical impact of the immune tumor microenvironment that may guide future immunotherapy trials. Methods: We analyzed transcriptomic data of 4 publicly available cohorts, accounting for more than 600 STS. Using a deconvolution method to estimate the tumor microenvironment composition with accurate scores depicting the immune profile of tumors, we established a robust immune classification. We divided the patients into 5 Sarcoma Immune Classes, labelled A1, A2, B, C1 and C2, which exhibit different extents and composition of immune infiltrate and cross histopathological classifications. We validated using immunohistochemichal (IHC) stainings for CD3, DC-Lamp, CD20, CD34 and PD-L1 the immune profiles of these groups on a 32-patients cohort. Results: Two groups (A1: 23.3% and A2: 27.1% of all tumors) exhibit a very low to low immune infiltrate for all cell types. Another class (B: 14.5% of all tumors) displays moderate immune infiltrate and a strong presence of endothelial cells. Finally, the remaining two groups (C1: 19.4% and C2: 15.6%) are highly infiltrated by all immune cell types. Notably, the immune high group C2 is associated with an overexpression of several immune checkpoints genes: PDCD1 (PD-1), CD274 (PD-L1), PDCD1LG2 (PD-L2), LAG3, HAVCR2 (TIM-3), CTLA4. On 93 patients, we showed that the immune-high group could be identified by the IHC-visible presence of tertiary lymphoid structures (TLS), defined as T cell aggregates juxtaposing B cell aggregates. The immune-high group also exhibited prolonged overall survival as compared with other groups. Using data from a phase 2 clinical trial with pembrolizumab, we show that patients with immune-high tumors survive longer under this treatment and that their tumors grow less. Conclusions: We have defined a novel immune-based classification of STS into 5 classes, among which an immune-high group characterized by a strong infiltration by all immune cell and expression of immune checkpoints, presence of TLS and longer overall survival. Patients with immune-high tumors survive longer than others when treated with PD-1 blockade. Legal entity responsible for the study: INSERM. Funding: This work was supported by the Institut National de la Santé et de la Recherche Médicale, the University Paris-Descartes, the University Pierre et Marie Curie, the Programme Cartes d'Identité des Tumeurs from the French League Against Cancer, grants from Institut National du Cancer (HTE-INSERM plan cancer, C16082DS), Association pour la Recherche sur le Cancer (ARC), Cancer Research for Personalized Medecine programme (CARPEM T8), "FONCER contre le cancer" programme, Labex Immuno-Oncology (LAXE62_9UMRS972 FRIDMAN). Disclosure: J. Adam: Consultant for AstraZeneca, Bayer, BMS, MSD and Roche and received research funding from MSD, Pfizer and Pierre Fabre. W-H. Fridman: Consultant for Medimmune, Novartis, Servier and Pierre Fabre. All other authors have declared no conflicts of interest.