Abstract B29: CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for therapeutic stratification of osteosarcoma patients in the French OS 2006 trial

Abstract

The French phase 3 trial (OS 2006) testing combining zoledronate (an osteoclast inhibitor) with chemotherapy and surgery did not improve the outcome of patients with osteosarcoma. To understand this unexpected result, the presence of infiltrating immune cells was investigated in 124 biopsies of patients enrolled in the trial. The percentage of CD68/CD163 tumor-infiltrating macrophages, CD8 lymphocytes, osteoclasts, and the PD1/PDL-1 checkpoint was assessed by immunohistochemistry. M1/M2 macrophage polarization was characterized by pSTAT1/CMAF staining. The expression of these biomarkers was correlated with clinical outcome. No statistical correlations were found with response to chemotherapy. High CD163 levels (>50% of cells per core; 43.8% of patients) were associated with CMAF nuclear expression and significantly correlated with greater overall survival (p=0.0025) and with longer metastasis progression-free survival (MPFS, p=0.0315) independently of diagnosis status (p=0.002). Only a trend was observed for patients with high CD68-positive cells (p=0.0582). CD8 staining was positive in >50% of cases with a median staining of 1%. Lower CD8 levels were associated with metastatic disease at diagnosis and only the presence of CD8-positive cells significantly correlated with improved overall survival in zoledronate-treated patients (p=0.0415). PD1/PDL-1 staining was negative in >80% of cases and was not correlated to prognosis. Finally, CD163-positive TAMs and CD8-positive cells (and not the PD1/PDL-1 checkpoint) are crucial predictive biomarkers in osteosarcoma. For the first time, we described a correlation between CD8-positive cells and zometa treatment. The immunohistochemical analysis of the microenvironment in osteosarcoma patient biopsies could represent a novel tool for therapeutic stratification. Citation Format: Anne Gomez-Brouchet, Claire Illac, Julia Gilhodes, Corinne Bouvier, Sébastien Aubert, Jean-Marc Guinebretiere, Béatrice Marie, Frédérique Larousserie, Natacha Entz-Werle, Gonzague de Pinieux, Thomas Filleron, Véronique Minard, Vincent Minville, Eric Mascard, François Gouin, Marta Jimenez, Marie-Cécile Ledeley, Sophie Piperno-Neumann, Laurence Brugieres, Françoise Redini. CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for therapeutic stratification of osteosarcoma patients in the French OS 2006 trial [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B29.

PLCE1 is a poor prognostic marker and may promote immune escape from osteosarcoma by the CD70-CD27 signaling pathway

“…The bone microenvironment of OS is composed of osteoclasts, osteoblasts, and hematopoietic cells, which are derived from monocytes/macrophages [34]. A variety of growth factors and cytokines released by these cells into the microenvironment play an important role in tumor development [35]. Therefore, a comprehensive analysis of the correlation between PLCE1 and TME can provide a reference for the pathogenesis of OS.…”

Targeted transcriptional profiling of the tumor microenvironment reveals lymphocyte exclusion and vascular dysfunction in metastatic osteosarcoma

“…The current literature states that OS tumors express PD-L1, PD-L2, PD-1, and exhibit varying degrees of lymphocyte abundance with increased CD8 T cells correlating with increased survival. [10][11][12][13] Bioinformatic analysis of DNA and RNA sequencing data shows that OS tumors express neoantigens, albeit at a low level. 14,15 Why OS patients with advanced and metastatic disease have not benefited from immune checkpoint blockade is an important, yet unresolved, question.…”

Lack of efficacy of neoadjuvant chemotherapy in adult patients with maxillo-facial high-grade osteosarcomas: A French experience in two reference centers

“…The identification of biomarkers could allow to detect tumor onset, progression and response to therapy for OS [46,58]. By predicting response to therapy, these biomarkers, as well as the immunohistochemical analysis of the microenvironment may represent novel tools for therapeutic stratification [59].…”