The Immune Microenvironment of Chordomas: An Immunohistochemical Analysis

Abstract

Chordomas are rare sarcomas that are usually treated by surgery and/or radiotherapy since these are chemo-resistant tumors, but immunotherapy could be a possible option for chordoma patients. However, few reports investigating the composition of the chordoma immune microenvironment exist. We immunohistochemically studied 81 chordomas regarding their immune microenvironment factors and compared them with clinicopathological data. Macrophages and CD4 cells were the most prominent inflammatory cell populations, followed by CD8 T cells, while CD20 B cells and high endothelial venules (MECA-79+) were less frequently found. PD-L1 (22C3) expression by inflammatory cells was found in 21 (26%) tumors and was associated with a larger tumor size. None of the cases showed the expression of PD-L1 by tumor cells. Survival analysis showed that younger patients had a better overall survival. Considering the immunohistochemical factors studied, higher CD8, the presence of PD-L1+ immune cells, and higher vascular density were adverse prognostic factors, but in multivariate analysis, only PD-L1+ immune cells retained prognostic significance. To conclude, chordoma tumor cells do not express PD-L1, but PD-L1+ immune cells seem to play a negative prognostic role, supporting the need for further studies in this field and the possible beneficial role of immunotherapy in these patients.

Coexpression of HHLA2 and PD-L1 on Tumor Cells Independently Predicts the Survival of Spinal Chordoma Patients

“…Considering that chordoma is histologically characterized by a rich myxoid stroma ( 45 ), these data strongly indicate that CAFs expressing B7H3 induce an inhibitory immune microenvironment to promote chordoma progression, thereby leading to adverse patient outcomes. This conjecture can be further supported by recent studies corroborating the prognostic significance of stromal content and immune cell infiltrates in spinal chordoma ( 29 , 34 , 45 , 46 ). Our subsequent studies will further characterize the CAF profile and evaluate their association with B7H3 expression as well as the immune features in chordoma tissues.…”

Multimodal profiling of chordoma immunity reveals distinct immune contextures

“…These studies identified myeloid cells and T cells as the most predominant immune cell populations in chordomas 7,23,27,28 . Similar to our findings, the majority of these immune cells was confined to the stroma, although both cell types could be found in the tumour nodules 6,7,28 . Moreover, other lymphoid cells such as NK cells (or innate lymphoid cells) and B cells were considered rare in chordomas 7,23,28 .…”

“…Recently, several studies have contributed to the improved understanding of the chordoma microenvironment, based on approaches including immunohistochemistry, multispectral immunofluorescence or single cell-RNA sequencing 6,7,23,27,28 . These studies identified myeloid cells and T cells as the most predominant immune cell populations in chordomas 7,23,27,28 . Similar to our findings, the majority of these immune cells was confined to the stroma, although both cell types could be found in the tumour nodules 6,7,28 .…”

“…Recent findings have provided evidence for the presence of conspicuous immune cell infiltration in chordomas 6,7 and, encouragingly, clinical responses of chordoma patients to checkpoint blockade immunotherapy targeting CTLA-4 and/or the PD-1/PD-L1 axis have been reported 8–12 . This is an intriguing observation as chordomas display a low mutational burden and are, instead, affected by gross chromosomal alterations 13–15 .…”

Linking Immunity with Genomics in Sarcomas: Is Genomic Complexity an Immunogenic Trigger?

“…Chordomas-a rare subtype of sarcoma of notochordal origin, which arise either in the skull base, the spine, or in the sacrum [80]-are, potentially the most immunologically "hot" sarcoma type. This is exemplified by their frequent infiltration with considerable amounts of CD4+ and CD8+ T cells, as well as with M1-like and M2-like TAMs [39][40][41][42]. In addition, at the protein level, PD-L1 is frequently expressed on tumor cells, whereas HLA class I is often expressed at varying degrees within a lesion [81].…”