DKK1 Promotes Tumor Immune Evasion and Impedes Anti–PD-1 Treatment by Inducing Immunosuppressive Macrophages in Gastric Cancer

Shi, Tao; Zhang, Yipeng; Wang, Yue; Song, Xueru; Wang, Hanbing; Zhou, Xiaoyu; Liang, Kaijie; Luo, Yuting; Che, Keying; Wang, Xuan; Pan, Yunfeng; Liu, Fangcen; Yang, Ju; Liu, Qin; Yu, Lixia; Yang, Ju; Wei, Jia

doi:10.1158/2326-6066.cir-22-0218

Cited by 37 publications

(23 citation statements)

References 63 publications

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“…Previous studies have shown that DKK1 promotes malignant phenotypes in hepatocellular carcinoma, including tumor angiogenesis, invasion, and metastasis. It has recently been demonstrated that DKK1 promotes immune escape and impairs anti‐PD‐1 therapeutic efficacy in GC 15 . Therefore, we further explored the effect of DKK1 on the malignant phenotype of AFPGC and found that it promoted AFP expression, as well as proliferation, migration, and EMT of AFPGC.…”

Section: Discussionmentioning

confidence: 93%

“…In addition, DKK1 has a more significant diagnostic value than AFP in hepatocellular carcinoma 14 . It has been recently demonstrated that DKK1 promotes immune escape and impairs anti‐PD‐1 therapeutic efficacy in GC 15 . However, there is no literature on the relationship between DKK1 and the malignant phenotype or AFP expression in AFPGC.…”

Section: Introductionmentioning

confidence: 99%

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Single‐cell characteristics and malignancy regulation of alpha‐fetoprotein‐producing gastric cancer

Mei

Wen

et al. 2023

Cancer Medicine

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Alpha-fetoprotein-producing gastric cancer (AFPGC) is a rare but highly malignant subtype of gastric cancer (GC) characterized by elevated serum alpha-fetoprotein (AFP) levels (>20 ng/mL). AFPGC accounts for 1.3%-15% of all GCs. 1 Patients with AFPGC have an aggressive clinical course, early occurrence of multiple organ metastases, primary multidrug resistance, and a poor prognosis. The 5-year survival rate of patients with stage IV AFPGC is 4.4%. 2 The pathogenesis of AFPGC is still not fully understood and effective therapeutic targets are lacking.In recent years, whole-exome sequencing (WES) has been used to study the genetic mutation profiles of AFPGC. In our previous study, we performed whole-exome sequencing of 29 cases of AFP-producing gastrointestinal cancer (AFPGI),

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Single‐cell characteristics and malignancy regulation of alpha‐fetoprotein‐producing gastric cancer

Mei

Wen

et al. 2023

Cancer Medicine

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“…In more recent studies, Dkk-1 has also been shown to potently modulate the immunological landscape of the tumor in favor of immune evasion ( 97 ). In this capacity, Dkk-1 has been reported to stimulate the activity of immune suppressive macrophages in gastric cancer ( 98 ), increase numbers of regulatory macrophages and T-cells in cholangiocarcinoma ( 99 ), and Dkk-1 expression is correlated with natural killer T-cell quiescence in prostate cancer ( 100 ). Interestingly, Dkk-1 has been shown to enhance the activity of immune suppressive myeloid derived suppressor cells (MDSCs) by directly targeting cWnt activity, resulting in greater numbers of intratumoral MDSCs that can participate in immune evasion ( 101 ).…”

Section: Discussionmentioning

confidence: 99%

Factors affecting the role of canonical Wnt inhibitor Dickkopf-1 in cancer progression

Doucet

Brubaker²,

Turner³

et al. 2023

Front. Oncol.

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BackgroundThe canonical Wnt inhibitor Dickkopf-1 (Dkk-1) has the capacity to modulate homeostasis between canonical and non-canonical Wnt pathways and also signal independently of Wnt. The specific effects of Dkk-1 activity on tumor physiology are therefore unpredictable with examples of Dkk-1 serving as either a driver or suppressor of malignancy. Given that Dkk-1 blockade may serve as a potential treatment for some types of cancer, we questioned whether it is possible to predict the role of Dkk-1 on tumor progression based on the tissue origin of the tumor.MethodsOriginal research articles that described Dkk-1 in terms a tumor suppressor or driver of cancer growth were identified. To determine the association between tumor developmental origin and the role of Dkk-1, a logistic regression was performed. The Cancer Genome Atlas database was interrogated for survival statistics based on tumor Dkk-1 expression.ResultsWe report that Dkk-1 is statistically more likely to serve as a suppressor in tumors arising from the ectoderm (p = 0.0198) or endoderm (p = 0.0334) but more likely to serve as a disease driver in tumors of mesodermal origin (p = 0.0155). Survival analyses indicated that in cases where Dkk-1 expression could be stratified, high Dkk-1 expression is usually associated with poor prognosis. This in part may be due to pro-tumorigenic role Dkk-1 plays on tumor cells but also through its influence on immunomodulatory and angiogenic processes in the tumor stroma.ConclusionDkk-1 has a context-specific dual role as a tumor suppressor or driver. Dkk-1 is significantly more likely to serve as a tumor suppressor in tumors arising from ectoderm and endoderm while the converse is true for mesodermal tumors. Patient survival data indicated high Dkk-1 expression is generally a poor prognostic indicator. These findings provide further support for the importance of Dkk-1 as a therapeutic cancer target in some cases.

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“…We in fact see greater representations of the aforementioned hubs after chemotherapy and after aPD1 in patients that are slow to progress (have more durable responses) compared to those that progress faster. From a clinical perspective it remains unclear whether the optimal strategy is to attempt to restrain the initial formation of anti-immunity hubs with agents that deprive the TME of immunosuppressive signals as has been attempted with neutralizing antibodies to IL-6 54 and DKK1 67 , or to try to directly stimulate the induction of pro-immunity hubs with agonist approaches like STING 68,69 or TLR7/8 70,71 . Towards the later approach, we find that programs for plasmacytoid and conventional dendritic cell subsets were present in hubs that favored slow progression (e.g.…”

Section: Discussionmentioning

confidence: 99%

Sequential pembrolizumab cooperates with platinum/5FU to remodel the tumor microenvironment in advanced gastric cancer: a phase II chemoimmunotherapy trial

Mehta

Min

et al. 2023

Preprint

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Adding anti-PD1 antibodies to 5-FU/platinum chemotherapy improves survival in a subset of advanced gastroesophageal adenocarcinoma (GEA) patients. Beyond PD-L1 expression and mismatch repair status we have limited insight into molecular predictors of response or the relative contribution of PD-1 blockade. We conducted an investigator sponsored phase II trial (n = 47) sequentially adding pembrolizumab to standard 5-FU/platinum in previously untreated advanced GEA (ClinicalTrials.gov:NCT04249739). With an overall response rate of 67% the activity paralleled phase III chemoimmunotherapy trials. To understand on-treatment tumor and immune adaptations patients underwent serial biopsy of the primary tumor, including baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab. We leveraged transcriptional profiling from 358,067 cells to identify multicellular networks of malignant, stromal, and immune cells after chemotherapy and concurrent chemoimmunotherapy. The relative usage of pro-tumor and anti-tumor interaction hubs differed between fast and slow progressing patients. Chemotherapy induced early on-treatment formation of hubs centered on tumor-reactive T-cell and M1-oriented macrophage interactions with pro-inflammatory cytokines in slow progressors. Faster progression was characterized by increased MUC5A and MSLN containing programs in tumor cells and M2-oriented macrophages with immunosuppressive stromal interactions. After adding pembrolizumab we observed increased CD8 T-cell infiltration by scRNAseq and multiplex immunofluorescence and development of an immunity hub involving co-variation of the tumor-reactive CXCL13 program and epithelial interferon-stimulated gene programs enriched in slow progressors. Together this data provides prospective evidence of differential early on-treatment evolution of the gastric immune microenvironment and nominates candidate cellular interactions for clinical targeting.

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DKK1 Promotes Tumor Immune Evasion and Impedes Anti–PD-1 Treatment by Inducing Immunosuppressive Macrophages in Gastric Cancer

Cited by 37 publications

References 63 publications

Single‐cell characteristics and malignancy regulation of alpha‐fetoprotein‐producing gastric cancer

Single‐cell characteristics and malignancy regulation of alpha‐fetoprotein‐producing gastric cancer

Factors affecting the role of canonical Wnt inhibitor Dickkopf-1 in cancer progression

Sequential pembrolizumab cooperates with platinum/5FU to remodel the tumor microenvironment in advanced gastric cancer: a phase II chemoimmunotherapy trial

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