PMID- 38272563 OWN - NLM STAT- MEDLINE DCOM- 20240129 LR - 20240315 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 12 IP - 1 DP - 2024 Jan 25 TI - Multimodal profiling of chordoma immunity reveals distinct immune contextures. LID - 10.1136/jitc-2023-008138 [doi] LID - e008138 AB - BACKGROUND: Chordomas are rare cancers from the axial skeleton which present a challenging clinical management with limited treatment options due to their anatomical location. In recent years, a few clinical trials demonstrated that chordomas can respond to immunotherapy. However, an in-depth portrayal of chordoma immunity and its association with clinical parameters is still lacking. METHODS: We present a comprehensive characterization of immunological features of 76 chordomas through application of a multimodal approach. Transcriptomic profiling of 20 chordomas was performed to inform on the activity of immune-related genes through the immunologic constant of rejection (ICR) signature. Multidimensional immunophenotyping through imaging mass cytometry was applied to provide insights in the different immune contextures of 32 chordomas. T cell infiltration was further evaluated in all 76 patients by means of multispectral immunofluorescence and then associated with clinical parameters through univariate and multivariate Cox proportional hazard models as well as Kaplan-Meier estimates. Moreover, distinct expression patterns of human leukocyte antigen (HLA) class I were assessed by immunohistochemical staining in all 76 patients. Finally, clonal enrichment of the T cell receptor (TCR) was sought through profiling of the variable region of TCRB locus of 24 patients. RESULTS: Chordomas generally presented an immune "hot" microenvironment in comparison to other sarcomas, as indicated by the ICR transcriptional signature. We identified two distinct groups of chordomas based on T cell infiltration which were independent from clinical parameters. The highly infiltrated group was further characterized by high dendritic cell infiltration and the presence of multicellular immune aggregates in tumors, whereas low T cell infiltration was associated with lower overall cell densities of immune and stromal cells. Interestingly, patients with higher T cell infiltration displayed a more pronounced clonal enrichment of the TCR repertoire compared with those with low T cell counts. Furthermore, we observed that the majority of chordomas maintained HLA class I expression. CONCLUSION: Our findings shed light on the natural immunity against chordomas through the identification of distinct immune contextures. Understanding their immune landscape could guide the development and application of immunotherapies in a tailored manner, ultimately leading to an improved clinical outcome for patients with chordoma. CI - (c) Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - van Oost, Siddh AU - van Oost S AUID- ORCID: 0000-0003-2281-5780 AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. AD - Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, Netherlands. FAU - Meijer, Debora M AU - Meijer DM AUID- ORCID: 0000-0002-6399-3084 AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. AD - Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, Netherlands. FAU - Ijsselsteijn, Marieke E AU - Ijsselsteijn ME AUID- ORCID: 0000-0002-8195-736X AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. FAU - Roelands, Jessica P AU - Roelands JP AUID- ORCID: 0000-0003-3631-2041 AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. FAU - van den Akker, Brendy E M W AU - van den Akker BEMW AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. FAU - van der Breggen, Ruud AU - van der Breggen R AUID- ORCID: 0000-0003-2110-6069 AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. FAU - Briaire-de Bruijn, Inge H AU - Briaire-de Bruijn IH AUID- ORCID: 0000-0002-9273-2828 AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. FAU - van der Ploeg, Manon AU - van der Ploeg M AUID- ORCID: 0000-0001-7150-3068 AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. FAU - Wijers-Koster, Pauline M AU - Wijers-Koster PM AUID- ORCID: 0009-0002-4758-7016 AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. FAU - Polak, Samuel B AU - Polak SB AUID- ORCID: 0000-0002-1683-7134 AD - University Neurosurgical Center Holland, Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands. FAU - Peul, Wilco C AU - Peul WC AUID- ORCID: 0000-0001-7274-1447 AD - University Neurosurgical Center Holland, Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands. FAU - van der Wal, Robert J P AU - van der Wal RJP AUID- ORCID: 0000-0002-2570-6988 AD - Department of Orthopaedic Surgery, Leiden University Medical Center, Leiden, Netherlands. FAU - de Miranda, Noel F C C AU - de Miranda NFCC AUID- ORCID: 0000-0001-6122-1024 AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. AD - Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, Netherlands. FAU - Bovee, Judith V M G AU - Bovee JVMG AUID- ORCID: 0000-0003-1155-0481 AD - Department of Pathology, Leiden University Medical Center, Leiden, Netherlands j.v.m.g.bovee@lumc.nl. AD - Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240125 PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Receptors, Antigen, T-Cell) SB - IM MH - Humans MH - *Chordoma/genetics/pathology/therapy MH - Gene Expression Profiling MH - Receptors, Antigen, T-Cell/genetics MH - Tumor Microenvironment PMC - PMC10824073 OTO - NOTNLM OT - Dendritic Cells OT - Immunotherapy OT - Sarcoma OT - T-Lymphocytes OT - Tumor Microenvironment COIS- Competing interests: No, there are no competing interests. EDAT- 2024/01/26 00:43 MHDA- 2024/01/29 06:43 PMCR- 2024/01/25 CRDT- 2024/01/25 20:52 PHST- 2024/01/02 00:00 [accepted] PHST- 2024/01/29 06:43 [medline] PHST- 2024/01/26 00:43 [pubmed] PHST- 2024/01/25 20:52 [entrez] PHST- 2024/01/25 00:00 [pmc-release] AID - jitc-2023-008138 [pii] AID - 10.1136/jitc-2023-008138 [doi] PST - epublish SO - J Immunother Cancer. 2024 Jan 25;12(1):e008138. doi: 10.1136/jitc-2023-008138.