PURPOSE: The IMMUNOSARC trial combined an antiangiogenic agent (sunitinib) with a PD1 inhibitor (nivolumab) in advanced sarcomas. Here, we present the first correlative studies of the soft-tissue sarcoma cohort enrolled in this trial. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded and peripheral blood samples were collected at baseline and week 13. Formalin-fixed paraffin-embedded samples were used for transcriptomics and multiplex immunofluorescence, whereas peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients. RESULTS: The density of intratumoral CD8+ T cells, measured by multiplexed immunophenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in the gene expressions of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1 and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at week 13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated 2 groups with distinct progression-free survival (PFS): 4.1 months [95% confidence interval, 3.5-not reached (NR)] versus 17 months (95% confidence interval, 12.0-NR), P = 0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples. CONCLUSIONS: Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T-cell density and the expression of several genes/proteins with relevance in the response to PD1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of antiangiogenics plus PD1 inhibitor therapy.

Department of Hematology University Hospital Son Espases Mallorca Spain

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Medical Oncology Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Department of Medical Oncology Fundacion Jimenez Diaz University Hospital Madrid Spain

Department of Medical Oncology Sant Pau Hospital Barcelona Spain

Department of Medical Oncology University Hospital 12 de Octubre Madrid Spain

Department of Medical Oncology University Hospital La Paz Madrid Spain

Department of Medical Oncology University Hospital Miguel Servet Zaragoza Spain

Department of Medical Oncology Vall d'Hebron University Hospital Barcelona Spain

Department of Oncology University of Torino Turin Italy

Department of Pathology Clinica Universidad de Navarra Pamplona Spain

Department of Pathology Medical School of the Catholic University of Valencia Valencia Spain

Department of Radiology University Hospital Virgen del Rocio Sevilla Spain

Fundación Institute Valenciano of Oncology Valencia Spain

Institute of Biomedicine of Seville Seville Spain

Joint Cancer Research Unit IVO CIPF Valencia Spain

Medical Oncology Unit Città della Salute e della Scienza di Torino Turin Italy

Research Health Institute of Fundacion Jimenez Diaz Madrid Spain

University Hospital General de Villalba Madrid Spain

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