Abstract
Background
Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometimes strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was thus to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6 in this disease.
Materials and methods
Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data.
Results
TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had a worse prognosis for overall survival.
Conclusions
UPS showed variation in CMTM6 copy number and CMTM6 expression. CMTM6 expression was significantly correlated with PD-L1 expression, especially with strong PD-L1 expression.
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Abbreviations
- CMTM6:
-
CKLF like MARVEL transmembrane domain containing 6
- FFPE:
-
Formalin-fixed, paraffin-embedded
- IS:
-
Intensity score
- PD-L1:
-
Programmed death-ligand 1
- PS:
-
Proportion score
- TCGA:
-
The Cancer Genome Atlas
- TIL:
-
Tumor-infiltrating lymphocytes
- UPS:
-
Undifferentiated pleomorphic sarcoma
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Acknowledgements
The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. We appreciate M. Tomita and M. Nakamizo at the Department of Anatomic Pathology, Kyushu University for providing technical support. We additionally thank the Research Support Center, Graduate School of Medical Sciences, Kyushu University, for providing the experimental devices.
Funding
The present study was supported by the Japan Society for the Promotion of Science KAKENHI (19H03444).
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SI, TI, KK, HY and YO designed this study and wrote the manuscript. SI, TI performed the experiments. SI, YT, YI, YS, TM, SK, DT, IK, TM, DK, TF, NS, ME, YM and YN collected the materials. SI, TI, KK, YY IK and YO performed histological re-evaluation of the samples and confirmed the diagnosis. SI, TI and YO supervised the experiments.
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The present study was approved by the Kyushu University Committee of Bioethics (approval no. 29-429 and 29-625; 2017).
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432_2021_3616_MOESM1_ESM.docx
Supplementary file1Supplementary Figure 1 Validations of PD-L1 and CMTM6 are shown. HE and IHC images of ×100 and ×400 for PD-L1 and CMTM6 are presented. For PD-L1 and CKLF-like MARVEL transmembrane domain containing 6 (CMTM6), the images show that the stromal cells were negative, while the tumor cells were positive. For CMTM6, UPS cells were not stained as strongly as the positive control of fallopian tube. Supplementary Figure 2 ROC curve of CD8-positive tumor-infiltrating lymphocytes (TILs) presented in a previous study. A cut-off of 25 was used. Supplementary Figure 3 Integrative Genomics Viewer of the copy number segment of undifferentiated pleomorphic sarcoma (UPS) cases in The Cancer Genome Atlas (TCGA) was obtained by using cBioPortal. Regarding the copy numbers of genes around chromosome 3p22 listed in Figure 1b and CKLF-like MARVEL transmembrane domain containing 6 (CMTM6), these appeared to exhibit copy number variation. Supplementary Figure 4 The relationship between PD-L1 and CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) expression. Supplementary Figure 5 ROC curves. (a) Strong PD-L1 expression (≥ 50%) and proportion score (PS) of CKLF-like MARVEL transmembrane domain containing 6 (CMTM6). (b) Strong PD-L1 expression (≥ 50%) and intensity score (IS) of CMTM6. (c) PD-L1 expression (≥ 1%) and PS of CMTM6. (d) PD-L1 expression (≥ 1%) and IS of CMTM6. (DOCX 4138 kb)
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Ishihara, S., Iwasaki, T., Kohashi, K. et al. The association between the expression of PD-L1 and CMTM6 in undifferentiated pleomorphic sarcoma. J Cancer Res Clin Oncol 147, 2003–2011 (2021). https://doi.org/10.1007/s00432-021-03616-4
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DOI: https://doi.org/10.1007/s00432-021-03616-4