Targeting CMTM6 Suppresses Stem Cell–Like Properties and Enhances Antitumor Immunity in Head and Neck Squamous Cell Carcinoma

Chen, Lei; Yang, Qi‐Chao; Li, Yicun; Yang, Leilei; Liu, Jian-Feng; Li, Hao; Xiao, Yao; Bu, Lin‐Lin; Zhang, Wenfeng; Sun, Zhi‐Jun

doi:10.1158/2326-6066.cir-19-0394

Cited by 103 publications

(122 citation statements)

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“…Elevated expression of CMTM6 was frequently accompanied with worse malignant phenomenon, such as with high AFP level, large tumor size, advanced TNM stage, vascular invasion in a large cohort of 619 HCC cases (In Zhu's study, only 75 HCC samples were collected). Our data was in line with other studies indicating that increased CMTM6 expression was presented in gliomaand Head and Neck Squamous Cell Carcinoma, and CMTM6 positivity was associated with shorter DFS and OS [12,15]. Collectively, we consider our data are more representative to show the expression of CMTM6 in HCC.…”

Section: Discussionsupporting

confidence: 92%

“…In contrast, the depletion of CMTM6 relieves T cell immunosuppression [14]. Additionally, it has been reported that elevated CMTM6 in head and neck squamous cell carcinoma and glioma is associated with a poor prognosis [12,15], and a potential therapeutic target for renal clear cell carcinoma [16]. CMTM6 expression in combination with PD-L1 expression can be used as a prognostic and therapeutic indicator in lung cancer and pancreatic ductal adenocarcinoma [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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Coexpression of CMTM6 and PD-L1 as a predictor of poor prognosis in macrotrabecular-massive hepatocellular carcinoma

Liu

Zhang

Chao

et al. 2020

Cancer Immunol Immunother

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The "macrotrabecular-massive" (MTM) pattern of hepatocellular carcinoma (HCC) has been suggested to represent a distinct HCC subtype and is associated with specific molecular features. Since the immune microenvironment is heterogenous in HCC, it is important to evaluate the immune microenvironment of this novel variant. CMTM6, a key regulator of PD-L1, is an important immunocheckpoint inhibitor. This study aimed to evaluate the prognostic effect of CMTM6/PD-L1 coexpression and its relationship with inflammatory cells in HCC. We analyzed 619 HCC patients and tumors were classified into MTM and non-MTM HCC subtypes. The expression levels of CMTM6 and PD-L1 in tumor and inflammatory cells were evaluated by immunohistochemistry. The density of inflammatory cells in the cancer cell nest was calculated. Tumoral PD-L1 expression and inflammatory cell density were higher in the MTM type than in the non-MTM type. CMTM6-high expression was significantly associated with shorter OS and DFS than CMTM6-low expression in the whole HCC patient population and the MTM HCC patient population. Moreover, MTM HCC patients with CMTM6/PD-L1 coexpression experienced a higher risk of HCC progression and death. In addition, CMTM6/PD-L1 coexpression was shown to be related to a high density of inflammatory cells. Notably, a new immune classification, based on CMTM6/PD-L1 coexpression and inflammatory cells, successfully stratified OS and DFS in MTM HCC. CMTM6/PD-L1 coexpression has an adverse effect on the prognosis of HCC patients, especially MTM HCC patients. Our study provides evidence for the combination of immune status assessment with anti-CMTM6 and anti-PD-L1 therapy in MTM HCC patients.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Coexpression of CMTM6 and PD-L1 as a predictor of poor prognosis in macrotrabecular-massive hepatocellular carcinoma

Liu

Zhang

Chao

et al. 2020

Cancer Immunol Immunother

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“…Overall, these studies suggest that CMTM6 is an important factor for immune invasion by tumor cells. Further studies suggest that knocking down CMTM6 results in decreased PD-L1 expression and increased infiltration of CD8+ and CD4+ T-cells, that in turn increased the anti-tumor immunity in HNSCC 23 . CMTM6 expression is also up regulated in high grade malignant glioma and it can be correlated with poor prognosis of glioma patients 24 .…”

Section: Discussionmentioning

confidence: 96%

CMTM6 drives cisplatin resistance in OSCC by regulating AKT mediated Wnt signaling

Mohapatra

Shriwas

Mohanty

et al. 2020

Preprint

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41Chemoresistance is one of the important factors for treatment failure in OSCC, which can 42 culminate in progressive tumor growth and metastatic spread. Rewiring tumor cells to undergo 43 drug-induced apoptosis is a promising way to overcome chemoresistance, which can be achieved 44 by identifying the causative factors for acquired chemoresistance. In this study, to explore the 45 key cisplatin resistance triggering factors, we performed global proteomic profiling of OSCC 46 lines representing with sensitive, early and late cisplatin-resistant patterns. The top ranked up-47 regulated protein appeared to be CMTM6. We found CMTM6 to be elevated in both early and 48 late cisplatin-resistant cells with respect to the sensitive counterpart. Analyses of OSCC patient 49 samples indicate that CMTM6 expression is upregulated in chemotherapy-non-responder tumors 50 as compared to chemotherapy-naïve tumors. Stable knockdown of CMTM6 restores cisplatin-51 mediated cell death in chemoresistant OSCC lines. Similarly, upon CMTM6 overexpression in 52 CMTM6KD lines, the cisplatin resistant phenotype was efficiently rescued. Mechanistically, it 53 was found that CMTM6 interacts with membrane bound Enolase-1 and stabilized its expression, 54 which in turn activates the AKT-GSK3β mediated Wnt signaling. CMTM6 triggers the 55 translocation of β-catenin into the nucleus, which elevates the Wnt target pro-survival genes like 56 Cyclin D, c-Myc and CD44. Moreover, incubation with lithium chloride, a Wnt signaling 57 activator, efficiently rescued the chemoresistant phenotype in CMTM6KD OSCC lines. In a 58 patient-derived cell xenograft model of chemoresistant OSCC, knock-down of CMTM6 restores 59 cisplatin induced cell death and results in significant reduction of tumor burden. CMTM6 has 60 recently been identified as a stabilizer of PD-L1 and henceforth it facilitates immune evasion by 61 tumor cells. Herewith for the first time, we uncovered another novel role of CMTM6 as one of 62 the major driver of cisplatin resistance. 63 64 65 66 67 68 69 70 71 72 Head and neck cancer is the sixth most common cancer worldwide with approximately 53,260 73 new cases are being reported in United States alone 1 . Almost 90% of HNSCC cancer cases are 74 Oral squamous cell carcinoma (OSCC) which has emerged as the most common cancer in 75 developing countries. In India, 80000 new OSCC cases are reported in each year with a 76 mortality of ~46000 2 . OSCC patients commonly present with locally advanced (stage III or IV) 77 disease. The treatment modalities of advanced OSCC are surgical removal of primary tumor 78 followed by chemo-radiotherapy 3 . However, neoadjuvant chemotherapy is commonly 79 prescribed for surgically unresectable OSCC tumors that provide more surgical options 4 . In spite 80 of having all these treatment modalities, the 5-year survival rate of advanced tongue OSCC 81 remains less than 50%, which indicates the development of resistance against existing therapy. 82 Chemoresistance is one of the major factors for treatment failure in...

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“…On the one hand, PD-L1, VISTA, and B7-H4 were correlated with the OSCC microenvironment, and their high expression indicates a suppressive status in OSCC ( 16 – 18 ). Additionally, CMTM6 is an important protein involved in the regulation of PD-L1, and CD317 is associated with B7-H4 and PD-L1 ( 36 , 37 ). On the other hand, Slug is one of the classical markers related to EMT ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of SHMT2 Is Associated With Poor Prognosis and Advanced Pathological Grade in Oral Squamous Cell Carcinoma

Wang

Yang

et al. 2020

Front. Oncol.

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This study focused on the expression of mitochondrial serine hydroxymethyltransferase (SHMT2) in oral squamous cell carcinoma (OSCC) and its correlation with clinical traits and the prognosis of OSCC patients. Immunochemical staining and Western blotting were used to quantify the expression of SHMT2 and related immune markers in OSCC. Using OSCC microarrays and The Cancer Genome Atlas (TCGA) database, we evaluated the association between SHMT2 and various clinical traits. We found that increased expression of SHMT2 was detected in OSCC and correlated with advanced pathological grade and recurrence of OSCC. By a multivariate Cox proportional hazard model, high expression of SHMT2 was shown to indicate a negative prognosis. In addition, in the OSCC microenvironment, increasing the expression of SHMT2 was associated with high expression levels of programmed cell death-ligand 1 (PD-L1), CKLF-like MARVEL transmembrane domain containing 6 (CMTM6), V-type immunoglobulin domain-containing suppressor (VISTA), B7-H4, Slug, and CD317. In the future, more effort will be required to investigate the role of SHMT2 in the OSCC microenvironment.

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Targeting CMTM6 Suppresses Stem Cell–Like Properties and Enhances Antitumor Immunity in Head and Neck Squamous Cell Carcinoma

Cited by 103 publications

References 50 publications

Coexpression of CMTM6 and PD-L1 as a predictor of poor prognosis in macrotrabecular-massive hepatocellular carcinoma

Coexpression of CMTM6 and PD-L1 as a predictor of poor prognosis in macrotrabecular-massive hepatocellular carcinoma

CMTM6 drives cisplatin resistance in OSCC by regulating AKT mediated Wnt signaling

Increased Expression of SHMT2 Is Associated With Poor Prognosis and Advanced Pathological Grade in Oral Squamous Cell Carcinoma

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