Fresh Tissue Multi-omics Profiling Reveals Immune Classification and Suggests Immunotherapy Candidates for Conventional Chondrosarcoma.

Abstract

PURPOSE:

There is still no standard nonsurgical regimen for conventional chondrosarcoma (CHS). We aimed to identify whether any CHSs have a favored microenvironment for immunotherapy via multidimensional evaluation of the immunologic characteristics of this tumor.

EXPERIMENTAL DESIGN:

We obtained 98 newly-diagnosed CHS fresh tumors from several institutions and performed comprehensive analysis of data from CyTOF, whole-exome sequencing, and flow cytometry in 22 cases. Clinical data from immunotherapy responders and nonresponders were compared to explore possible biomarkers of immunotherapy response. Mechanism studies were conducted to interpret the biomarker phenotype.

RESULTS:

Based on the integrated data of single-cell CyTOF and flow cytometry, the CHS immune-microenvironment phenotypes were classified into three groups: subtype I, the "granulocytic-myeloid-derived suppressor cell (G-MDSC) dominant" cluster, with high number of HLA-DR- CD14- myeloid cells; subtype II, the "immune exhausted" cluster, with high exhausted T-cell and dendritic-cell infiltration; and subtype III, the "immune desert" cluster, with few immune cells. Immune cell-rich subtypes (subtype I and II) were characterized by IDH mutation, pathologic high grade, and peritumoral edema, while subtype I cases were exclusively featured by myxoid transformation. In clinical practice involving 12 individuals who received PD-1 antibody immunotherapy, all of the 3 cases with controlled diseases were retrospectively classified as subtype II. In mechanism, IDH mutation significantly elevated chemokine levels and immune-cell infiltration in immune-inactivated tumors.

CONCLUSIONS:

This study is the first to provide immune characterization of CHS, representing a major step to precise immunotherapy against this malignancy. Immunotherapy is promising for the "immune exhausted" subtype of patients with CHS.

• Authors: Binghao Li, Guoqi Li, Xiaobo Yan, Dan Zhu, Patrick P Lin, Zenan Wang, Hao Qu, Xuexin He, Yanbiao Fu, Xiuliang Zhu, Peng Lin, Jiangnan Zhang, Xiaoya Li, Hui Dai, Huabiao Chen, Mark C Poznansky, Nong Lin, Zhaoming Ye
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 23 Pg. 6543-6558 (12 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34426437 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Topics

• Chondrosarcoma (genetics, therapy)
• Humans
• Immunotherapy (methods)
• Myeloid-Derived Suppressor Cells
• Retrospective Studies
• Tumor Microenvironment (genetics)