Manipulating the Wnt/β-catenin signaling pathway to promote anti-tumor immune infiltration into the TME to sensitize ovarian cancer to ICB therapy

Wall, Jaclyn; Meza-Pérez, Selene; Scalise, Carly Bess; Katre, Ashwini A.; Londoño, Angelina I.; Turbitt, William J.; Randall, Troy D.; Norian, Lyse A.; Arend, Rebecca C.

doi:10.1016/j.ygyno.2020.10.031

Cited by 35 publications

(24 citation statements)

References 25 publications

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“…For experimental analysis, it has been discovered for a good performance in CRC with fused Rspo. 291 Further in-depth studies respectively included the combined usage of CGX1321 and immune checkpoint blockade therapy to treat ovarian cancer (but the results were unsatisfactory), 292 and liposome encapsulation as a vehicle to deliver CGX1321 to treat cancer stem cells (with expected results). 293 …”

Section: Promising Preclinical Targeted Therapiesmentioning

confidence: 99%

Wnt/β-catenin signaling in cancers and targeted therapies

Chen

et al. 2021

Sig Transduct Target Ther

272

160

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Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/β-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling. However, current facts indicate that the clinical translations of Wnt/β-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/β-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/β-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.

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Section: Promising Preclinical Targeted Therapiesmentioning

confidence: 99%

Wnt/β-catenin signaling in cancers and targeted therapies

Chen

et al. 2021

Sig Transduct Target Ther

272

160

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“…As for immunity, four aspects were analyzed respectively, including tumor immune infiltration, tumor microenvironment, immune checkpoint molecules and immune cells pathway. Previous articles reported that tumor immune infiltration and tumor microenvironment might be involved in OC tumorigenesis and response to immunotherapy [ 48 , 49 ]. Our results indicated that the CACNA1C expression was significantly associated with B cell infiltration, CD4 + T cell infiltration, neutrophil infiltration, macrophage infiltration, and dendritic cell infiltration for tumor immune infiltration and markedly related to ESTIMATEScore and StromalScore for tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

CACNA1C is a prognostic predictor for patients with ovarian cancer

Chang

Dong

2021

J Ovarian Res

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Background CACNA1C, as a type of voltage-dependent calcium ion transmembrane channel, played regulatory roles in the development and progress of multiple tumors. This study was aimed to analyze the roles of CACNA1C in ovarian cancer (OC) of overall survival (OS) and to explore its relationships with immunity. Methods Single gene mRNA sequencing data and corresponding clinical information were obtained from The Cancer Genome Atlas Database (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Gene set enrichment analysis (GSEA) was used to identify CACNA1C-related signal pathways. Univariate and multivariate Cox regression analyses were applied to evaluate independent prognostic factors. Besides, associations between CACNA1C and immunity were also explored. Results CACNA1C had a lower expression in OC tumor tissues than in normal tissues (P < 0.001), with significant OS (P = 0.013) and a low diagnostic efficiency. We further validated the expression levels of CACNA1C in OC by means of the ICGC dataset (P = 0.01), qRT-PCR results (P < 0.001) and the HPA database. Univariate and multivariate Cox hazard regression analyses indicated that CACNA1C could be an independent risk factor of OS for OC patients (both P < 0.001). Five significant CACNA1C-related signaling pathways were identified by means of GSEA. As for genetic alteration analysis, altered CACNA1C groups were significantly associated with OS (P = 0.0169), progression-free survival (P = 0.0404), disease-free survival (P = 0.0417) and disease-specific survival (P = 9.280e-3), compared with unaltered groups in OC. Besides, CACNA1C was dramatically associated with microsatellite instability (MSI) and immunity. Conclusions Our results shed light on that CACNA1C could be a prognostic predictor of OS in OC and it was closely related to immunity.

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“…It suggested that aberrant activated Wnt pathway would promote an exclude immune phenotype which was unfavorable for the efficacy of ICIs 30 , 31 . Meanwhile, Wnt inhibitor had shown its role in enhancing the efficacy of ICIs 32 . These observations suggested that both tumor intrinsic characteristics and tumor microenvironment changed profoundly after chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC

He¹,

Chen²,

Zhao³

et al. 2021

Theranostics

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Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

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Manipulating the Wnt/β-catenin signaling pathway to promote anti-tumor immune infiltration into the TME to sensitize ovarian cancer to ICB therapy

Cited by 35 publications

References 25 publications

Wnt/β-catenin signaling in cancers and targeted therapies

Wnt/β-catenin signaling in cancers and targeted therapies

CACNA1C is a prognostic predictor for patients with ovarian cancer

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC

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