Predictive and Dynamic Signature for Antiangiogenics in Combination with a PD1 Inhibitor in Soft-Tissue Sarcoma: Correlative Studies Linked to the IMMUNOSARC Trial.

Autor:	Moura DS; Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain., Lopez-Marti JM; Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain., Benesova I; Department of Immunology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic., de Andrea C; Department of Pathology, Clinica Universidad de Navarra, Pamplona, Spain., di Lernia D; Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain., Lacerenza S; Institute of Biomedicine of Seville (IBiS; US, CSIC, HUVR), Seville, Spain., Mondaza-Hernandez JL; Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain., Martin-Ruiz M; Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain., Ramirez-Calvo M; Fundación Institute Valenciano of Oncology, Valencia, Spain., Grignani G; Medical Oncology Unit, Città della Salute e della Scienza di Torino, Turin, Italy., Martinez-Trufero J; Department of Medical Oncology, University Hospital Miguel Servet, Zaragoza, Spain., Redondo A; Department of Medical Oncology, University Hospital La Paz, Madrid, Spain., Valverde C; Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain., Stacchiotti S; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Lopez-Pousa A; Department of Medical Oncology, Sant Pau Hospital, Barcelona, Spain., Lopez-Guerrero JA; Fundación Institute Valenciano of Oncology, Valencia, Spain.; Joint Cancer Research Unit IVO-CIPF, Valencia, Spain.; Department of Pathology, Medical School of the Catholic University of Valencia, Valencia, Spain., Gutierrez A; Department of Hematology, University Hospital Son Espases, Mallorca, Spain., Encinas-Tobajas V; Department of Radiology, University Hospital Virgen del Rocio, Sevilla, Spain., Hindi N; Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain.; Department of Medical Oncology, Fundacion Jimenez Diaz University Hospital, Madrid, Spain.; University Hospital General de Villalba, Madrid, Spain., Sangiolo D; Department of Oncology, University of Torino, Turin, Italy., Lopez-Martin JA; Department of Medical Oncology, University Hospital 12 de Octubre, Madrid, Spain., Strizova ZO; Department of Immunology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic., Martin-Broto J; Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain.; Department of Medical Oncology, Fundacion Jimenez Diaz University Hospital, Madrid, Spain.; University Hospital General de Villalba, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Nov 15; Vol. 30 (22), pp. 5192-5206.
DOI:	10.1158/1078-0432.CCR-24-1782
Abstrakt:	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. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu