Abstract 4955: Impact of PD-1, PD-L1 and EBI3 on prognosis in a cohort of localized high grade undifferentiated pleomorphic sarcoma patients
Authors: Boudou-Rouquette Pascaline , Jouinot Anne , Audard Virginie , Letourneur Franck , Parfait Béatrice , Goldwasser François , Terris Benoit , Laurent-Puig Pierre , Alexandre Jérôme , Leroy Karen , Pasmant Eric , Devergne Odile , Larousserie Frederique 
Published: August 2019

Abstract
Introduction: Studies of soft-tissue sarcomas (STS) and therapeutic outcomes are limited by their rarity and heterogeneity. Despite intensive treatment, including chemotherapy, surgery and radiation therapy, 30% of patients develop recurrent disease, and the outcome of the patients with recurrent or metastatic sarcomas remains poor. The SARC028 phase II, multicenter trial of pembrolizumab reported promising activity in selected histologic subtypes of advanced STS, including undifferentiated pleomorphic sarcoma (UPS). On the other hand, multicentre phase II trial (PEMBROSARC) found that PD-1 inhibition has limited activity in selected STS (UPS and LMS and GIST). The application of immune checkpoint blockade in sarcoma is in its infancy and we do not yet understand which patients will benefit from these therapies.
Methods: We explored the degree of PD-L1, PD-1, and CD8 expression in tumor tissue and microenvironment and their clinical impact in a retrospective analysis of 50 UPS sarcoma samples, at diagnosis. PD-L1 status was assessed on whole sections of fixed tissue. We also studied expression by tumors cells of two heterodimeric cytokines IL-27 (EBI3 / p28) and IL-35 (EBI3 / p35), known for inducing the expression of immune checkpoints. Their expression was investigated by analyzing the expression of their shared subunit EBI3 by immunohistochemistry. Patients presented with grade 3 FNCLCC, localized, sarcoma of the extremities, with a high risk of local and distant recurrence and were treated in a relatively homogeneous way (surgery followed by adjuvant radiation therapy and chemotherapy).
Results: The median overall survival was 63.4 months after a median follow-up of 42.0 months (range, 3.7- 108.3 months). The PD-L1 score on tumor cells (E1L3N, Cell Signaling) was negative in 94% of cases, with only 1 that had more than 10% PD-L1-positive tumor cells. Three semi-quantitative scores were performed on the immune cells: PD-L1 (same antibody): score 0 (62%), 1 (34%), 2 (4%); PD-1 (PD-1 NAT, Abcam): score 0 (52%), 1 (32%), 2 (16%) and CD8 + (C8/144B, Dako): score 0 (4%), 1 (36%), 2 (58%), NE (2%). PD-1 expression was associated with CD 8 infiltration (chi2 p=0.047). The EBI3 score on tumor cells was positive (&gt;30% positive cells) in 6% of cases and correlated with worse overall survival (p=0.04) and progression-free survival (p&lt;0.01), whereas PD1 (expressed by T cells), PD-L1 (expressed by infiltrating immune cells or tumor cells) and CD8 infiltration lacked prognostic significance. We are now integrating data from Affymetrix microarray gene expression and whole exome to investigate the molecular differences on tumors.
Conclusion: This study suggests that targeting immune checkpoints downstream of IL-27/IL-35, different from PD1 may benefit to some UPS patients.
Note: This abstract was not presented at the meeting.
Citation Format: Pascaline Boudou-Rouquette, Anne Jouinot, Virginie Audard, Franck Letourneur, Béatrice Parfait, François Goldwasser, Benoit Terris, Pierre Laurent-Puig, Jérôme Alexandre, Karen Leroy, Eric Pasmant, Odile Devergne, Frederique Larousserie. Impact of PD-1, PD-L1 and EBI3 on prognosis in a cohort of localized high grade undifferentiated pleomorphic sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4955.