Research Papers:

Tumoral immune-infiltrate (IF), PD-L1 expression and role of CD8/TIA-1 lymphocytes in localized osteosarcoma patients treated within protocol ISG-OS1

Emanuela Palmerini _, Claudio Agostinelli, Piero Picci, Stefano Pileri, Teresa Marafioti, Pier-Luigi Lollini, Katia Scotlandi, Alessandra Longhi, Maria Serena Benassi and Stefano Ferrari

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Oncotarget. 2017; 8:111836-111846. https://doi.org/10.18632/oncotarget.22912

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Emanuela Palmerini1, Claudio Agostinelli2, Piero Picci1, Stefano Pileri3,4, Teresa Marafioti5, Pier-Luigi Lollini6, Katia Scotlandi1, Alessandra Longhi1, Maria Serena Benassi1 and Stefano Ferrari1

1Chemotherapy Unit, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy

2Haematopathology Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy

3Haematopathology Unit, European Institute of Oncology, Milan, Italy

4Bologna University School of Medicine, Bologna, Italy

5University College London Cancer Institute, London, United Kingdom

6Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy

Correspondence to:

Emanuela Palmerini, email: [email protected]

Keywords: osteosarcoma; PD-1; PD-L1; CD8; tumor microenvironment

Received: July 19, 2017    Accepted: November 15, 2017    Published: December 04, 2017


Background: We hypothesized that immune-infiltrates were associated with superior survival, and examined a primary osteosarcoma tissue microarrays (TMAs) to test this hypothesis.

Methods: 129 patients (pts) with localized osteosarcoma treated within protocol ISG-OS1 were included in the study. Clinical characteristics, expression of CD8, CD3, FOXP3, CD20, CD68/CD163 (tumor associated macrophage, TAM), Tia-1 (cytotoxic T cell), CD303 (plasmacytoid dendritic cells: pDC), Arginase-1 (myeloid derived suppressor cells: MDSC), PD-1 on immune-cells (IC), and PD-L1 on tumoral cells (TC) and IC were analysed and correlated with outcome.

Results: Most of the cases presented tumor infiltrating lymphocytes (TILs) (CD3+ 90%; CD8+ 86%). Tia-1 was detected in 73% of the samples. PD-L1 expression was found in 14% patients in IC and 0% in TC; 22% showed PD-1 expression in IC.

With a median follow-up of 8 years (range 1-13), the 5-year overall survival (5-year OS) was 74% (95% CI 64-85). Univariate analysis showed better 5-year OS for: a) pts with a good histologic response to neoadjuvant chemotherapy (p = 0.0001); b) pts with CD8/Tia1 tumoral infiltrates (p = 0.002); c) pts with normal alkaline phosphatas (sALP) (p = 0.04). After multivariate analysis, histologic response (p = 0.007) and CD8/Tia1 infiltration (p = 0.01) were independently correlated with survival. In the subset of pts with CD8+ infiltrate, worse (p 0.02) OS was observed for PD-L1(IC)+ cases.

Conclusions: Our findings support the hypothesis that CD8/Tia1 infiltrate in tumor microenvironment at diagnosis confers superior survival for pts with localized osteosarcoma, while PD-L1 expression is associated with worse survival.

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