The special immune microenvironment of tumor budding and its impact on prognosis in gastric adenocarcinoma

Zhang, Nana; Wang, Depu; Duan, Yixin; Ayarick, Vivian Adiila; Cao, Meng; Wang, Ying; Zhang, Guanjun; Wang, Yili

doi:10.1016/j.prp.2020.152926

“…Furthermore, in lung cancer and germ cell tumors, the presence of B cell follicles in TLSs promote the activated mechanisms of germinal centers somatic hypermutation and class switch recombination, accompanied by the plasma cells' generation [13,40].Thus, a high density of TLSs appears to be a good biomarker of the tumor immune microenvironment in which cellular and humoral immune reactions occur. And its favourable prognostic role also has been verified in many different cancers types, including the oral squamous cell carcinoma [32], skin merkel cell carcinoma [41] lung cancer [6,13,14] colorectal cancer [39], pancreatic cancer [26]and the breast cancer [37,38].The present study showed that the TLSs distributed significantly higher in the tumor invasive edge than the tumor center.…”

Section: P R E P R I N Tsupporting

confidence: 69%

“…A total of 147 cases were incorporated into this study. The detailed information were described in the table Ⅰ of our previous study (supplementary table I) [26]. The survival time of patients was between 1 and 123 months, and the median survival time was 50.6 months.…”

Section: Patients and Tissue Specimensmentioning

confidence: 99%

The relationship of the tertiary lymphoid structures with the tumor-infiltrating lymphocytes and its prognostic value in gastric cancer

Zhang

¹

,

Zhang

²

,

Wang

³

et al. 2021

Arch Med Sci

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IntroductionTo explore the relationship between the tertiary lymphoid structures (TLSs) and tumor-infiltrating lymphocytes (TILs), and their distribution characteristics as well as the prognostic value in gastric cancer (GC).Material and methodsThe TLSs and four subtypes of TILs were assessed by immunohistochemistry (IHC) staining. The presence of MECA-79 positive high endothelial venules (HEVs) identified among the ectopic lymphocyte aggregation area in the GC tissue was defined as a valid TLSs.The number of labeled TILs were observed in 5 fields of the most positive cells in tumor center, invasive edge and within the TLSs, respectively, at a field of vision×40.ResultsThe TLSs distributed significantly higher in the tumor invasive edge than the tumor center (P <0.001). Similarly, the infiltrating density of CD8+T cells and GrB+T cells were highly distributed in the tumor infiltrating edge than the tumor center. While the total number of TILs and the FOXP3+T cells were on the contrary. There was a positive correlation between the density of TLSs and TILs either in the location or the immune phenotype. And a higher frequency of TILs and TLSs often associated with the favorable clinicopathologic parameters. Multivariate analysis revealed that the density of TILs (P= 0.019) and TLSs (P= 0.037) were the independent prognostic predictor for GC patients.ConclusionsThe formation of TLSs predicts an advantageous immune system function and can be considered as a novel biomarker to stratify the overall survival risk of untreated GC patients and as a marker of efficient immunotherapies.

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“…Growing evidence suggests that cancer cells in general are under increased oxidative stress compared to normal cells [ 45 ]. The redox status in CRC is tightly associated with the tumor environmental trait, inflammatory infiltration, and tumor budding which is defined as a detached cluster of fewer than 5 cells at the invasive front of a tumor [ 46 , 47 ]. It has been indicated that CRC with high grade of budding generally presented with higher levels of oxidative stress [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Improvement in Redox Homeostasis after Cytoreductive Surgery in Colorectal Adenocarcinoma

Salehi

¹

,

Mirmiranpour

²

,

Rabizadeh

³

et al. 2021

Oxidative Medicine and Cellular Longevity

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Colorectal cancer (CRC) as one the most common cancer type is associated with oxidative stress. Surgery is the only curative modality for early-stage CRC. The aim of this study was to evaluate the oxidative damage biomarkers as well as enzymatic and nonenzymatic antioxidants in patients with CRC before and after tumor resection and in healthy controls. 60 patients with stage I/II colorectal adenocarcinoma and 43 healthy controls were recruited in this study. We measured plasma levels of oxidative damage biomarkers, including advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), malondialdehyde (MDA), and oxidized low-density lipoprotein (ox-LDL) at baseline and after tumor removal. We also evaluated the plasma activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) as enzymatic antioxidants and the ferric reducing antioxidant power (FRAP) assay for nonenzymatic antioxidant capacity. Patients with CRC had significantly higher AGE, AOPP, MDA, and ox-LDL and also FRAP levels and higher SOD and GPx and lower CAT activity levels compared to healthy controls ( p < 0.05 ). We did not observe any statistically significant correlation between redox biomarkers and the size and stage of the tumor. AGEs ( 72.49 ± 4.7 vs. 67.93 ± 8.8 , p < 0.001 ), AOPP ( 137.64 ± 21.9 vs. 119.08 ± 33.1 , p < 0.001 ), MDA ( 3.56 ± 0.30 vs. 3.05 ± 0.33 , p < 0.001 ), and ox-LDL ( 19.78 ± 0.97 vs. 16.94 ± 1.02 , p < 0.001 ) concentrations reduced significantly after tumor removal. The largest effect sizes were found in ox-LDL ( d = − 2.853 , 95% CI 2.50-3.19) and MDA ( d = − 1.617 , 95% CI 0.43-0.57). Serum FRAP levels ( 1097.5 ± 156.7 vs. 1239.3 ± 290 , p < 0.001 ) and CAT ( 2.34 ± 0.34 vs. 2.63 ± 0.38 , p < 0.001 ), GPx ( 102.37 ± 6.58 vs. 108.03 ± 6.95 , p < 0.001 ), and SOD ( 5.13 ± 0.39 vs. 5.53 ± 0.31 , p < 0.001 ) activity levels increased significantly after surgery. The largest effect sizes among antioxidants were seen in SOD ( d = 1.135 , 95% CI 0.46-0.34) and GPx ( d = 0.836 , 95% CI 0.35-0.23). This study indicated that patients with colorectal cancer had higher levels of oxidative stress and antioxidant activity compared to healthy controls. After surgical resection of tumor, we observed a substantial improvement in redox homeostasis.

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“…Tumor budding in CRC is defined as a single tumor cell or a cell cluster of up to four tumor cells, assessed in one hotspot (in a field measuring 0.785 mm 2 ) at the invasive front [ 12 , 13 ]. Studies have indicated a close link between tumor budding and a distinctive immune-suppressing microenvironment that promotes tumor invasion in gastric adenocarcinoma [ 14 ], stage I lung adenocarcinoma [ 15 ], pancreatic cancer [ 16 ], and CRC [ 17 ]. Nevertheless, the crosstalk between fibroblasts and tumor buds, and the mechanism through which the crosstalk occurs remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Tumor bud-derived CCL5 recruits fibroblasts and promotes colorectal cancer progression via CCR5-SLC25A24 signaling

Gao

¹

,

Zhong

²

,

Long

³

et al. 2022

J Exp Clin Cancer Res

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Background Tumor budding is included in the routine diagnosis of colorectal cancer (CRC) and is considered a tumor prognostic factor independent of TNM staging. This study aimed to identify the fibroblast-mediated effect of tumor bud-derived C–C chemokine ligand 5 (CCL5) on the tumor microenvironment (TME). Methods Recruitment assays and a human cytokine array were used to detect the main cytokines that CRC tumor buds secrete to recruit fibroblasts. siRNA transfection and inhibitor treatment were used to investigate the role of fibroblast CCL5 receptors in fibroblast recruitment. Subsequently, transcriptome sequencing was performed to explore the molecular changes occurring in fibroblasts upon stimulation with CCL5. Finally, clinical specimens and orthotopic xenograft mouse models were studied to explore the contribution of CCL5 to angiogenesis and collagen synthesis. Results Hematoxylin–eosin staining and immunochemistry revealed a higher number of fibroblasts at the invasive front of CRC tissue showing tumor budding than at sites without tumor budding. In vitro experiments demonstrated that CCL5 derived from tumor buds could recruit fibroblasts by acting on the CCR5 receptors on fibroblasts. Tumor bud-derived CCL5 could also positively regulate solute carrier family 25 member 24 (SLC25A24) expression in fibroblasts, potentially activating pAkt-pmTOR signaling. Moreover, CCL5 could increase the number of α-SMAhigh CD90high FAPlow fibroblasts and thus promote tumor angiogenesis by enhancing VEGFA expression and making fibroblasts transdifferentiate into vascular endothelial cells. Finally, the results also showed that CCL5 could promote collagen synthesis through fibroblasts, thus contributing to tumor progression. Conclusions At the invasive front of CRC, tumor bud-derived CCL5 can recruit fibroblasts via CCR5-SLC25A24 signaling, further promoting angiogenesis and collagen synthesis via recruited fibroblasts, and eventually create a tumor-promoting microenvironment. Therefore, CCL5 may serve as a potential diagnostic marker and therapeutic target for tumor budding in CRC.

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The special immune microenvironment of tumor budding and its impact on prognosis in gastric adenocarcinoma

Cited by 16 publications

References 53 publications

The relationship of the tertiary lymphoid structures with the tumor-infiltrating lymphocytes and its prognostic value in gastric cancer

The relationship of the tertiary lymphoid structures with the tumor-infiltrating lymphocytes and its prognostic value in gastric cancer

Improvement in Redox Homeostasis after Cytoreductive Surgery in Colorectal Adenocarcinoma

Tumor bud-derived CCL5 recruits fibroblasts and promotes colorectal cancer progression via CCR5-SLC25A24 signaling

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