CMTM6-Deficient Monocytes in ANCA-Associated Vasculitis Fail to Present the Immune Checkpoint PD-L1

Zeisbrich, Markus; Chevalier, Nina; Sehnert, Bettina; Rizzi, Marta; Venhoff, Nils; Thiel, Jens; Voll, Reinhard

doi:10.3389/fimmu.2021.673912

Cited by 18 publications

(10 citation statements)

References 45 publications

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“…However, single-cell sequencing results showed that CMTM6 was widely expressed in other immune cells, and it was in fact predominated in granulocytes and macrophages. For example, Markus Zeisbrich and colleagues found that CMTM6 in monocytes can affect the expression of membrane PD-L1 ( 13 ). Therefore, on other immune cells, whether CMTM6 regulates PD-L1 stability and whether it depends on PD-L1 for its functions needs to be systematically investigated.…”

Section: Discussionmentioning

confidence: 99%

“…CMTM6 is an M-shaped four-transmembrane protein containing the MARVEL transmembrane domain ( 10–12 ). After the initial discovery of the ability of CMTMT6 to regulate PD-L1, this function was confirmed in monocytes ( 13 ) as well as in other types of cancer cells ( 14 ). Extensive clinical analysis also found a significant positive correlation between CMTM6 and PD-L1 expression in tumors ( 15–20 ).…”

Section: Introductionmentioning

confidence: 95%

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Suppression of Tumor or Host Intrinsic CMTM6 Drives Antitumor Cytotoxicity in a PD-L1–Independent Manner

Long

Chen

et al. 2022

Cancer Immunology Research

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CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) is known to be 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 as a target for therapy, are still largely unknown. Here, we show that CMTM6 expression increased with tumor progression in both patients and mice. Ablation of CMTM6 significantly reduced human and murine tumor growth in a manner dependent on T-cell 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. Without the PD-1/PD-L1 axis, CMTM6 suppression still significantly dampened tumor growth dependent on cytotoxic cells. Further, we identified that CMTM6 was widely expressed on immune cells. T-cell CMTM6 levels increased with sustained immune activation and intratumoral immune exhaustion and affected T cell–intrinsic PD-L1 levels. Host CMTM6 knockout significantly restrained tumor growth in a manner dependent on CD8+ T cells and 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 involved in antitumor immunity with or without the PD-1/PD-L1 axis and that gene therapy targeting CMTM6 is a promising strategy for cancer immunotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Suppression of Tumor or Host Intrinsic CMTM6 Drives Antitumor Cytotoxicity in a PD-L1–Independent Manner

Long

Chen

et al. 2022

Cancer Immunology Research

View full text Add to dashboard Cite

show abstract

“…However, single-cell sequencing results showed that CMTM6 was widely expressed in other immune cells, and was in fact predominated in granulocytes and macrophages. For example, Markus Zeisbrich et al found that CMTM6 in monocytes can affect the expression of membrane PD-L1 ( 13 ). Therefore, the function of CMTM6 on these immune cells is also worthy of investigation.…”

Section: Discussionmentioning

confidence: 99%

“…CMTM6 is an M-shaped fourtransmembrane protein containing the MARVEL transmembrane domain (10)(11)(12). The PD-L1 regulation effect reported initially was subsequently confirmed in monocytes (13) as well as in other species of tumor cells (14). Extensive clinical analysis also found a significant positive correlation between CMTM6 and PD-L1 expression in tumors (15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 87%

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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“…Cellular defects, e.g. in the regulation of the inhibitory immune checkpoint molecule programmed death-ligand 1 (PD-L1) in monocytes promote the development of highly activated T cells in AAV ( 6 ). Along with this, the continuous and/or altered presentation of PR3 to highly activated T cells accompanied by local inflammation-induced B and plasma cell survival, this sets the prerequisite for the loss of tolerance towards PR3 with subsequent production of ANCA in GPA ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

Immunogenic cell death as driver of autoimmunity in granulomatosis with polyangiitis

2022

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Cell death and dysregulated clearance of dead cells play essential roles in the induction of chronic inflammatory processes and autoimmune diseases. Granulomatosis with polyangiitis (GPA), a neutrophil-driven autoimmune disorder, is characterized by necrotizing inflammation predominantly of the respiratory tract and an anti-neutrophil cytoplasmic autoantibody (ANCA)-associated systemic necrotizing vasculitis. Defective regulation of neutrophil homeostasis and cell death mechanisms have been demonstrated in GPA. Disturbed efferocytosis (i.e., phagocytosis of apoptotic neutrophils by macrophages) as well as cell death-related release of damage-associated molecular patterns (DAMP) such as high mobility group box 1 (HMGB1) contribute to chronic non-resolving inflammation in GPA. DAMP have been shown to induce innate as well as adaptive cellular responses thereby creating a prerequisite for the development of pathogenic autoimmunity. In this review, we discuss factors contributing to as well as the impact of regulated cell death (RCD) accompanied by DAMP-release as early drivers of the granulomatous tissue inflammation and autoimmune responses in GPA.

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CMTM6-Deficient Monocytes in ANCA-Associated Vasculitis Fail to Present the Immune Checkpoint PD-L1

Cited by 18 publications

References 45 publications

Suppression of Tumor or Host Intrinsic CMTM6 Drives Antitumor Cytotoxicity in a PD-L1–Independent Manner

Suppression of Tumor or Host Intrinsic CMTM6 Drives Antitumor Cytotoxicity in a PD-L1–Independent Manner

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

Immunogenic cell death as driver of autoimmunity in granulomatosis with polyangiitis

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