Sequential modulation of the Wnt/β-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance

Dholakia, Jhalak; Scalise, Carly Bess; Katre, Ashwini A.; Goldsberry, Whitney N.; Meza-Pérez, Selene; Randall, Troy D.; Norian, Lyse A.; Novak, Lea; Arend, Rebecca C.

doi:10.1016/j.ygyno.2021.09.026

Cited by 15 publications

(9 citation statements)

References 60 publications

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“…That is, the expression pattern of phospho-AKT is opposite to that of MHC-I proteins (Chandrasekaran et al, 2019). Activation of the Wnt signaling pathway is associated with decreased MHC-I expression and c-myc-mediated HLA downregulation (Versteeg et al, 1988;Yang et al, 2020;Dholakia et al, 2022). This is consistent with the results we observed in clinical biopsies and mouse model samples, that is, during the response period of MAPK-targeted therapy, MHC-I antigen presentation increased significantly relative to baseline samples.…”

Section: Discussionsupporting

confidence: 89%

Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma

Song

et al. 2022

Front. Pharmacol.

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Immune checkpoint blockade and MAPK-targeted combined therapy is a promising regimen for advanced melanoma patients. However, the clinical benefit from this combo regimen remains limited, especially in patients who acquired resistance to MAPK-targeted therapy. Here, we systematically characterized the immune landscape during MAPK-targeted therapy in patients and mouse melanoma models. We observed that both the abundance of tumor-infiltrated T cells and the expression of immune-related genes were upregulated in the drug-responsive period, but downregulated in the resistance period, implying that acquired drug resistance dampens the antitumor immune response. Further transcriptomic dissection indicated that loss of MHC-I antigen presentation on tumor cells plays a critical role in the reduction of T cell infiltration during drug resistance. Survival analysis demonstrates that loss of antigen presentation and reduction of T-cell infiltration during acquired drug resistance are associated with poorer clinical response and prognosis of anti-PD-1 therapy in melanoma patients. In addition, we identified that alterations in the MAPK inhibitor resistance-related oncogenic signaling pathway closely correlated with deficiency of MHC-I antigen presentation, including activation of the PI3K-mTOR, MAPK, and Wnt pathways. In conclusion, our research illuminates that decreased infiltration of T cells is associated with acquired drug resistance during MAPK-targeted therapy, which may underlie the cross-resistance to immune checkpoint blockade.

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Section: Discussionsupporting

confidence: 89%

Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma

Song

et al. 2022

Front. Pharmacol.

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“…The key to this signaling cascade is the Wnt ligand, which binds to receptors belonging to the Frizzled family or ROR1/ROR2 and RYK families. This interaction controls the downstream signal cascade (classical/non-classical), ultimately expanding its influence on the cytoskeleton, transcriptional control of proliferation and differentiation, and organelle dynamics [ 69 ]. Abnormal Wnt signaling is related to colorectal cancer.…”

Section: Wnt Pathway-related Biochemical Processmentioning

confidence: 99%

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

et al. 2022

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Background The Wnt signaling pathway is a complex network of protein interactions that functions most commonly in embryonic development and cancer, but is also involved in normal physiological processes in adults. The canonical Wnt signaling pathway regulates cell pluripotency and determines the differentiation fate of cells during development. The canonical Wnt signaling pathway (also known as the Wnt/β-catenin signaling pathway) is a recognized driver of colon cancer and one of the most representative signaling pathways. As a functional effector molecule of Wnt signaling, the modification and degradation of β-catenin are key events in the Wnt signaling pathway and the development and progression of colon cancer. Therefore, the Wnt signaling pathway plays an important role in the pathogenesis of diseases, especially the pathogenesis of colorectal cancer (CRC). Objective Inhibit the Wnt signaling pathway to explore the therapeutic targets of colorectal cancer. Methods Based on studying the Wnt pathway, master the biochemical processes related to the Wnt pathway, and analyze the relevant targets when drugs or inhibitors act on the Wnt pathway, to clarify the medication ideas of drugs or inhibitors for the treatment of diseases, especially colorectal cancer. Results Wnt signaling pathways include: Wnt/β-catenin or canonical Wnt signaling pathway, planar cell polarity (Wnt-PCP) pathway and Wnt-Ca2+ signaling pathway. The Wnt signaling pathway is closely related to cancer cell proliferation, stemness, apoptosis, autophagy, metabolism, inflammation and immunization, microenvironment, resistance, ion channel, heterogeneity, EMT/migration/invasion/metastasis. Drugs/phytochemicals and molecular preparations for the Wnt pathway of CRC treatment have now been developed. Wnt inhibitors are also commonly used clinically for the treatment of CRC. Conclusion The development of drugs/phytochemicals and molecular inhibitors targeting the Wnt pathway can effectively treat colorectal cancer clinically.

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“…Apart from interferon-γ and interferon-α responses, the IL-6/JAK/STAT3 signaling pathway suppresses the anti-tumor immune response ( 75 ), the NOD-like receptor signaling pathway affects the stages of inflammation-associated tumorigenesis ( 76 ), and the Toll-like receptor signaling pathway was a crucial access to promote invasion in OC patients ( 77 ). As previous studies and GSEA results have shown, elafin is correlated with interferon-γ and lipopolysaccharide, which increases HLA/MHC I expression for the improved recognition by CD8+ T cells as an important component towards enhanced tumor antigenicity ( 78 ). How elafin participates in the immune-related pathways would be attributed to its location and domains.…”

Section: Discussionmentioning

confidence: 89%

Elafin is related to immune infiltration and could predict the poor prognosis in ovarian cancer

Xie

Tan

et al. 2023

Front. Endocrinol.

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BackgroundOvarian cancer (OC) is the most lethal gynecologic malignancy, yet the clinical results for OC patients are still variable. Therefore, we examined how elafin expression affects the patients’ prognoses and immunotherapy responses in OC, which may facilitate treatment selection and improve prognosis.MethodsThe elafin mRNA expression profile was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Elafin’s prognostic potential and its relationship with clinical variables were investigated using Kaplan–Meier survival curves, time-dependent receiver operating characteristic curves as well as univariate and multivariate Cox regression models. As validation, protein expression in the tumor and adjacent tissues of OC patients was investigated by using immunohistochemistry (IHC). Comprehensive analyses were then conducted to explore the correlation between immune infiltration and elafin expression.ResultsA higher mRNA expression of elafin was associated with an unfavorable prognosis in TCGA cohort and was validated in GSE31245 and IHC. Moreover, elafin was indicated as an independent risk factor for OC. A significantly higher protein expression of elafin was detected in the adjacent tissues of OC patients with shorter overall survival (OS). The immune-related pathways were mainly enriched in the high-elafin-mRNA-expression group. However, the mRNA expression of elafin was favorably correlated with indicators of the immune filtration and immunotherapy response, which also proved better immunotherapy outcomes.ConclusionThe high elafin expression was associated with an unfavorable OS, while it also indicated better immunotherapy responses. Thus, the detection of elafin is beneficial to diagnosis and treatment selection.

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Sequential modulation of the Wnt/β-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance

Cited by 15 publications

References 60 publications

Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma

Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

Elafin is related to immune infiltration and could predict the poor prognosis in ovarian cancer

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