Abstract 3857: Characterization of immune cell biomarkers in undifferentiated pleomorphic sarcoma
Authors: Barreto Carmelia M. , Solis-Soto Luisa M. , Salazar Ruth , Gite Swati , Parra Edwin R. , Mino Barbara , Ingram Davis , Wani Khalida M. , Leung Cheuk H. , Lin Heather , Wistuba Ignacio I. , Lazar Alexander , Wang Wei-Lien 
Published: September 2020

Abstract
Background: Undifferentiated pleomorphic sarcoma (UPS) are genetically complex sarcomas often showing a relatively higher immune infiltration among sarcomas, and a demonstrated benefit for immunotherapy in a subset of patients. This study characterizes the immune microenvironment of UPS including tumor infiltrating lymphocytes (TILs), as well as immune checkpoint (IC) and related biomarkers.
Methods: We used FFPE surgical resected UPS from 90 patients (43 primary, 28 recurrence and 19 metastasis) placed in a tissue microarray and stained with immunohistochemistry for the following biomarkers: IC (stimulatory: OX40 & ICOS; inhibitory: PD-L1, LAG3, IDO1, & PD1), TILs (CD3 & CD8), monocytes-macrophages (CD163), Adenosine Pathway (CD73 & CD39), and pSTAT3. We scored TIL and IC biomarkers as positive cell densities, and PD-L1, pSTAT3, CD73 and CD39 as percentage of expression in malignant cells. Clinicopathological data and clinical outcome were available for all patients. Spearman correlation was used to assess the correlation between two biomarkers. Cox proportional hazard regression models were used to identify the prognostic biomarkers for overall survival (OS), recurrence-free survival (RFS), and metastasis-free survival (MFS).
Results: In our cohort, PD-L1, pSTAT3, CD73 and CD39 positive expression (cut-off ≥1%) was 19, 73 78 and 68% respectively. These biomarkers were positively correlated with immune infiltrates: CD3 (p=0.013, 0.009, 0.009, &lt;.001), CD8 (p=0.004, 0.016, &lt;.001, &lt;.001) and ICOS (p=0.005, 0.222, 0.007, 0.022). CD73 and CD39 were also positively correlated with both CD163 (p=0.001, &lt;.001) and PD-1 (p=0.012, &lt;.001). In recurrent tumors, smaller tumors had higher CD3, CD8, ICOS and PD-1 (p=0.011, 0.045, 0.013, 0.045). In metastatic tumor, CD163 and OX40 were positively correlated with age (p=0.045, 0.019). OX40 was inversely correlated with tumor size (p=0.04). ICOS positively correlated with PD-1, PD-L1 and CD39 (p&lt;.001, 0.002, 0.003) in primary tumors; with IDO1 and PD1 (p=0.012, &lt;.001) in recurrent tumors; and with PD-L1 expression (p=0.031) in metastatic tumors. Low CD3, CD8, CD163 densities (cut-off median) were associated with inferior OS (HR: 3.19 [1.37, 7.42]; p=0.007), RFS (HR: 2.79 [1.21, 6.42], p=0.016), and MFS (HR: 2.42 [1.05, 5.56]; p=0.038) after adjusting for size, respectively. Low CD73 and PD-L1 (cut-off median) were associated with inferior OS (HR 3.03 [HR: 1.21, 7.61], p=0.018), RFS (HR: 2.59 [1.06, 6.36]; p=0.037), and MFS (HR: 2.43 [1.00, 5.89], p=0.049), respectively.
Conclusions: In this study, we characterized the immune cell infiltrates and the expression of PD-L1, pSTAT3, CD73 and CD39 in UPS. These biomarkers differentially correlated with clinicopathological characteristics in primary, recurrent and metastatic tumors. Lower TILs and low CD73/PD-L1 expression were associated with inferior survival outcomes.
Citation Format: Carmelia M. Barreto, Luisa M. Solis-Soto, Ruth Salazar, Swati Gite, Edwin R. Parra, Barbara Mino, Davis Ingram, Khalida M. Wani, Cheuk H. Leung, Heather Lin, Ignacio I. Wistuba, Alexander Lazar, Wei-Lien Wang. Characterization of immune cell biomarkers in undifferentiated pleomorphic sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3857.