Co-Expression with Membrane CMTM6/4 on Tumor Epithelium Enhances the Prediction Value of PD-L1 on Anti-PD-1/L1 Therapeutic Efficacy in Gastric Adenocarcinoma

Wang, Ziqi; Peng, Zhi; Liu, Qiyao; Guo, Zixia; Menatola, Merey; Su, Jing; Li, Ting; Ge, Qing; Wang, Pingzhang; Shen, Lin; Jin, Rong

doi:10.3390/cancers13205175

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…In metastatic tumors, transcription factors FOS and JUN were associated with metastatic progression and kinases ERBB2 and CDK12 could identify metastatic tissue compared to primary tumor tissue (27). found that tumor cell surface expression of the molecules CMTM4/CMTM6 positively regulates expression of PD-L1 (42). Co-expression of CMTM4/6 with PD-L1 correlated with poorer prognoses, but these patients have higher early efficacy with immune checkpoint blockade therapy, making these molecules a potential prognostic indicator for favorable treatment.…”

Section: Epithelial Cell Response To Inflammationmentioning

confidence: 99%

“…Most groups obtained primary gastric cancer tissues from patients to generate scRNAseq data (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Some utilized previously published primary tumor datasets for further analysis (36)(37)(38)(39)(40)(41)(42)(43). Others transcriptionally profiled "liquid biopsies" of metastatic ascites fluid taken from gastric cancer patients (44,45).…”

Section: Introductionmentioning

confidence: 99%

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Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

Hoft

Pherson²,

DiPaolo³

2022

Front. Immunol.

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Single-cell RNA sequencing (scRNAseq) technology is still relatively new in the field of gastric cancer immunology but gaining significant traction. This technology now provides unprecedented insights into the intratumoral and intertumoral heterogeneities at the immunological, cellular, and molecular levels. Within the last few years, a volume of publications reported the usefulness of scRNAseq technology in identifying thus far elusive immunological mechanisms that may promote and impede gastric cancer development. These studies analyzed datasets generated from primary human gastric cancer tissues, metastatic ascites fluid from gastric cancer patients, and laboratory-generated data from in vitro and in vivo models of gastric diseases. In this review, we overview the exciting findings from scRNAseq datasets that uncovered the role of critical immune cells, including T cells, B cells, myeloid cells, mast cells, ILC2s, and other inflammatory stromal cells, like fibroblasts and endothelial cells. In addition, we also provide a synopsis of the initial scRNAseq findings on the interesting epithelial cell responses to inflammation. In summary, these new studies have implicated roles for T and B cells and subsets like NKT cells in tumor development and progression. The current studies identified diverse subsets of macrophages and mast cells in the tumor microenvironment, however, additional studies to determine their roles in promoting cancer growth are needed. Some groups specifically focus on the less prevalent ILC2 cell type that may contribute to early cancer development. ScRNAseq analysis also reveals that stromal cells, e.g., fibroblasts and endothelial cells, regulate inflammation and promote metastasis, making them key targets for future investigations. While evaluating the outcomes, we also highlight the gaps in the current findings and provide an assessment of what this technology holds for gastric cancer research in the coming years. With scRNAseq technology expanding rapidly, we stress the need for periodic review of the findings and assess the available scRNAseq analytical tools to guide future work on immunological mechanisms of gastric carcinogenesis.

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Section: Epithelial Cell Response To Inflammationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

Hoft

Pherson²,

DiPaolo³

2022

Front. Immunol.

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“…Patients with high expression of CMTM6 in macrophages can obtain the greatest benefit from PD-1/PD-L1 blockade in colorectal cancer (28) and in NSCLC (41). Wang et al found that Co-expression of CMTM6 or CMTM4 with PD-L1 on tumor cells can predict the therapeutic efficacy of anti-PD-1/L1 in gastric adenocarcinoma (33). Another study showed that high coexpression of CMTM6 and PD-L1 in stromal compartment was significantly associated with longer survival in treated patients (38).…”

Section: Potential Clinical Application Of Cmtm6 and Cmtm4mentioning

confidence: 99%

“…It was reported that CMTM6 and CMTM4 are directly and/or indirectly regulates the expression of PD-L1 in cancer cells and in different immune cells including DCs, macrophages, and monocytes ( 13 , 28 , 33 , 77 ). Furthermore, CMTM6 expression was positively correlated with PD-L1 expression in various cancers including HNSCC ( 18 ), lung cancer ( 30 , 69 ), gliomas ( 20 ), gastric cancer ( 33 , 36 ), and colon cancer ( 40 ) ( Table 1 ). Similarly, CMTM4 was also identified as the positive regulator of PD-L1 in many tumors, such as in HCC ( 88 ) and in HNSCC ( 42 ).…”

Section: The Expression Of Cmtm6/4 Is Associated With the Immune-rela...mentioning

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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“…(18,19,(21)(22)(23)(24). Remarkably, CMTM6/PD-L1 coexpression suggested a poorer prognosis (20,(25)(26)(27), but instead a better prognosis when ICB therapies intervened (28)(29)(30). However, some contradictory findings have also been reported, indicating a complex role for CMTM6 in clinical cancers such as non-small cell lung cancer (NSCLC) (31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

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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Co-Expression with Membrane CMTM6/4 on Tumor Epithelium Enhances the Prediction Value of PD-L1 on Anti-PD-1/L1 Therapeutic Efficacy in Gastric Adenocarcinoma

Cited by 10 publications

References 34 publications

Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

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

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

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