Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity

Wang, Hanfeng; Yang, Fan; Chen, Wei-Hao; Lv, Zheng; Wu, Shengpan; Xuan, Yundong; Wang, Chenfeng; Lu, Yongliang; Guo, Tao; Shen, Donglai; Zhang, Fan; Huang, Qingbo; Gao, Yu; Li, Hongzhao; Ma, Xin; Wang, Qianqian; Huang, Yan; Zhang, Xu

doi:10.1080/2162402x.2021.2011673

Cited by 22 publications

(21 citation statements)

References 55 publications

(60 reference statements)

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“…In addition, some potential interaction molecules and functions of CMTM6 recently discovered (35)(36)(37)(38)(39) are also potential explanations. For example, CMTM6 may influence tumor immunogenicity by affecting tumor genome stability (37) and thus participate in tumor immunity. These findings warrant further investigation to ascertain the circumstances under which CMTM6 functions independently of PD-L1.…”

Section: Discussionmentioning

confidence: 98%

“…And as a MARVEL domain-containing membrane protein, CMTM6 may also be involved in regulating processes such as vesicle transport and tight junctions (11). In addition, some potential interaction molecules and functions of CMTM6 recently discovered (35)(36)(37)(38)(39) are also potential explanations. For example, CMTM6 may influence tumor immunogenicity by affecting tumor genome stability (37) and thus participate in tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

“…The exosomal CMTM6 derived from oral squamous cell carcinoma cells augmented macrophage M2 differentiation by activating the ERK1/2 pathway ( 35 ). Studies also observed that CMTM6 inhibited p21 ubiquitination ( 36 ), genomic stability ( 37 ), and the mTOR pathway ( 38 ) to influence tumor cell growth, and acts on vimentin to affect tumor cell migration and invasion ( 39 ). And Hu-Antigen R ( 40 ) and neuropilin-1 ( 41 ) can affect the expression of CMTM6 at transcription and protein levels, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Suppression of tumor/host intrinsic CMTM6 drives anti-tumor cytotoxicity in a PD-L1 independent manner

Long

Chen

et al. 2022

Preprint

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CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) has been identified as a regulator of membranal programmed death ligand 1 (PD-L1) stability and a factor associated with malignancy progression, but the effects and mechanisms of CMTM6 on tumor growth, as well as its potential for therapy, are still largely unknown. Here, we show that tumor CMTM6 increased with progression in both clinical patients and mice. Ablation of CMTM6 resulted in significant retardation of human and murine tumor growth dependent on T-lymphocyte immunity. Tumor CMTM6 suppression broke resistance to immune checkpoint inhibitors and remodeled the tumor immune microenvironment, as specific antitumor cytotoxicity was enhanced and contributed primarily to tumor inhibition. Further, without the PD-1/PD-L1 axis, CMTM6 suppression still significantly dampened tumor growth dependent on cytotoxic cells. Notably, we identified that CMTM6 was widely expressed on immune cells. T-cell CMTM6 increased with sustained immune activation and intratumoral immune exhaustion and affected the T-cell-intrinsic PD-L1 levels. Host CMTM6 knockout significantly restrained tumor growth dependent on CD8+ T-cells, and similarly, not entirely dependent on PD-L1. Thus, we developed and evaluated the antitumor efficacy of CMTM6-targeting adeno-associated virus (AAV), which effectively mobilized antitumor immunity and could be combined with various antitumor drugs. Our findings reveal that both tumor and host CMTM6 are deeply involved in tumor immunity with or without the PD-1/PD-L1 axis and that gene therapy targeting CMTM6 is a promising strategy for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Suppression of tumor/host intrinsic CMTM6 drives anti-tumor cytotoxicity in a PD-L1 independent manner

Long

Chen

et al. 2022

Preprint

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“…In patients with melanoma and non-small cell lung cancer, CMTM6 protein abundance was associated with increased T cell abundance in pre-treatment biopsies 42,43 , but its role as a predictive biomarker remains unclear 44 , likely due to its dual role in co-regulating PD-L1 and CD58. Recent studies indicate a possible role of CMTM6 in genome stability and the mTOR pathway, and suggest that inhibition (or degradation) of total CMTM6 may reduce tumor severity and metastatic behavior 45,46 . Our study highlights a complex role of CMTM6 in both pro-and anti-tumor immunity regulation; thus, focusing on specific interactions may be important in the development of therapeutics targeting CMTM6.…”

Section: Discussionmentioning

confidence: 99%

The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity

Melms

Rogava

et al. 2022

Preprint

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The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 co-immunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary co-stimulatory signals required for response to PD-1 blockade (e.g. CD28), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2-expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.

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“…CMTM6 has been shown to have oncogenic properties and be highly expressed in various tumors such as head and neck squamous cell carcinoma (HNSCC) ( 18 ), glioma ( 19 , 20 ), colorectal cancer ( 21 ), ovarian cancer ( 22 ), oral squamous cell carcinoma (OSCC) ( 23 , 24 ), hepatocellular carcinoma (HCC) ( 25 , 26 ), and renal cancer ( 27 ) ( Table 1 ). The high expression of CMTM6 is closely correlated with poor prognosis in different tumors ( 18 – 20 , 24 , 25 , 27 , 29 , 32 – 37 , 39 ) ( Table 1 ). In addition to directly affect tumor proliferation, the tumor-promoting effect of CMTM6 may also be accomplished by indirectly regulating TME ( 18 , 40 , 41 ).…”

Section: Introductionmentioning

confidence: 99%

CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment

Zhang

Dai

2022

Front. Immunol.

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The tumor microenvironment (TME) plays crucial roles in regulating tumor occurrence, progress, metastasis and drug resistance. However, it remains largely elusive how the components of TME are regulated to govern its functions in tumor biology. Here, we discussed how the two novel functional proteins, chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 6 (CMTM6) and CMTM4, which involved in the post-translational regulation of PD-L1, modulate the TME functions. The roles of CMTM6 and CMTM4 in regulating TME components, including immune cells and tumor cells themselves were discussed in this review. The potential clinical applications of CMTM6 and CMTM4 as biomarkers to predict therapy efficacy and as new or combined immunotherapy targets are also highlighted. Finally, the current hot topics for the biological function of CMTM6/4 and several significant research directions for CMTM6/4 are also briefly summarized in the review.

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Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity

Cited by 22 publications

References 55 publications

Suppression of tumor/host intrinsic CMTM6 drives anti-tumor cytotoxicity in a PD-L1 independent manner

Suppression of tumor/host intrinsic CMTM6 drives anti-tumor cytotoxicity in a PD-L1 independent manner

The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity

CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment

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