The association between the expression of PD-L1 and CMTM6 in undifferentiated pleomorphic sarcoma

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.

Keywords: CMTM6; Copy number; PD-L1; Prognosis; Undifferentiated pleomorphic sarcoma.

Fig. 1

Data obtained from The Cancer Genome Atlas (TCGA). a The mRNAs of PD-L1 and CMTM6 (RSEM) correlated positively. b A list of the genes encoding mRNAs coexpressed with CMTM6 mRNA was obtained using cBioPortal. c The relationship between the mRNA expression and copy number variation of CMTM6

Fig. 2

Representative histological and immunohistochemical features: a Pleomorphic and haphazard. b Bizarre tumor giant cells. c–e IS is the intensity score of CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) expression in IHC. CMTM6 IS 0, CMTM6 IS 1, and CMTM6 IS 2 are presented in order from the left. f–h PD-L1 expression [(< 1%), (≤ 1 and < 50%), and (≥ 50%)]

Fig. 3

a The results of copy number analysis. CMTM6 copy number of the tumor cells was calculated comparing with the CMTM6 copy number of skeletal muscle tissue. The copy number of skeletal muscle tissue was determined as 2 and presented as a reference. b, c The relationship between CMTM6 copy number and CMTM6 proportion score (PS) or intensity score (IS)

Fig. 4

The outcome of survival analysis. Prognostic information for 41 cases was available. a Overall survival and proportion score (PS) of CKLF-like MARVEL transmembrane domain containing 6 (CMTM6). b Overall survival and intensity score (IS) of CMTM6. c Disease-free survival and PS of CMTM6. d Disease-free survival and IS of CMTM6

Fig. 5

Chart subgrouping undifferentiated pleomorphic sarcoma (UPS) according to PD-L1 and CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) expression and the level of CD8-positive TILs