Tumor‐infiltrating CD8<sup>+</sup> T‐cell density is an independent prognostic marker for oral squamous cell carcinoma

Sasaki, Shota; Hiratsuka, Hiroyoshi; Koike, Kazushige; Tsuchihashi, Kei; Sonoda, Tomoko; Ogi, Kazuhiro; Miyakawa, Akira; Kobayashi, Jun’ichi; Kaneko, Takeshi; Igarashi, Takayoshi; Hasegawa, Tadashi; Miyazaki, Akira

doi:10.1002/cam4.1889

Cited by 124 publications

(112 citation statements)

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“…However, the objective response rates to checkpoint blockade immunotherapy only range from 16 to 25% [11,12]. As recent studies indicated, immunerelated biomarkers could define not only the patients' immune state, but also the biological behavior of HNSCC [13][14][15]. For example, tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment could contribute to improved prognosis [14].…”

Section: Introductionmentioning

confidence: 99%

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

She

Kong

et al. 2020

Cancer Cell Int

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Background: Immune-related genes (IRGs) were linked to the prognosis of head and neck squamous cell carcinoma (HNSCC). This study aimed to identify the effects of an immune-related gene signature (IRGS) that can predict the of HNSCC prognosis. Methods: The expression data of 770 HNSCC patients from the TCGA database and the GEO database were used. To explore a predictive model, the Cox proportional hazards model was applied. The Kaplan-Meier survival analysis, as well as univariate and multivariate analyses were performed to evaluate the independent predictive value of IRGS. To explore biological functions of IRGS, enrichment analyses and pathway annotation for differentially expressed genes (DEGs) in different immune groups were applied, as well as the immune infiltration. Results: A prognostic signature comprising 27 IRGs was generated. IRGS significantly stratified HNSCC patients into high and low immune risk groups in regard to overall survival in the training cohort (HR = 3.69, 95% CI 2.73-4.98, P < 0.001). Likewise, IRGS could be linked to the prognosis of HNSCC in patients of the validation cohort (HR = 1.84, 95% CI 1.21-2.81, P < 0.01). Even after adjusting for TNM stage, IRGS was maintained as an independent predictor in the multivariate analysis (HR = 3.62, 95% CI 2.58-5.09, P < 0.001), and in the validation cohort (HR = 1.73, 95% CI 1.12-2.67, P = 0.014). The IFN-α response, the IFN-γ response, IL-2/STAT5 signaling, and IL-6/JAK/STAT3 signaling were all negatively correlated with the immune risk (P < 0.01). Immune infiltration of the high-risk group was significantly lower than that of the low-risk group (P < 0.01). Most notably, the infiltration of CD8 T cells, memory-activated CD4 T cells, and regulatory T cells was strongly upregulated in the low immune risk groups, while memory resting CD4 T cell infiltration was downregulated (P < 0.01). Conclusion: Our analysis provides a comprehensive prognosis of the immune microenvironments and outcomes for different individuals. Further studies are needed to evaluate the clinical application of this signature.

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Section: Introductionmentioning

confidence: 99%

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

She

Kong

et al. 2020

Cancer Cell Int

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“…Because HLA class I expression at the IF was associated with decreased cancer cell proliferation and metastasis based on survival, it might exert a protective effect against cancer. In addition, we previously reported that CD8⁺ T cell density at the IF was an indicator of tumor recurrence and prognosis 19 . The cases analyzed in our previous and present studies largely overlapped, but in the present study, we analyzed the relationship between CD8⁺ T cell density and HLA class I expression.…”

Section: Discussionmentioning

confidence: 72%

“…In addition, tissue sections were incubated with a primary mAb against pan‐cytokeratin (1:200, clone AE1/AE3; Abcam) to detect multiple cytokeratins and identify tumor cells. CD8 + T cells were stained according to our previous report 19 …”

Section: Methodsmentioning

confidence: 99%

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Prognostic value of HLA class I expression in patients with oral squamous cell carcinoma

et al. 2020

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Human leukocyte antigen (HLA) class Ⅰ molecules play a central role in anticancer immunity, but their prognostic value in oral squamous cell carcinoma (OSCC) remains unclear. We examined HLA class I expression in 2 distinct tumor compartments, namely, the tumor center and invasive front, and evaluated the association between its expression pattern and histopathological status in 137 cases with OSCC. Human leukocyte antigen class Ⅰ expression was graded semiquantitatively as high, low, and negative. At the invasive front of the tumor, HLA class I expression was high in 72 cases (52.6%), low in 44 cases (32.1%), and negative in 21 cases (15.3%). The HLA class I expression in the tumor center was high in 48 cases (35.0%), low in 58 cases (42.4%), and negative in 31 cases (22.6%). The 5-year overall survival and diseasespecific survival rates were good in cases with high HLA class I expression at the invasive front; however, there was no significant difference in survival based on HLA class I expression in the tumor center. In addition, high HLA class I expression was correlated with high CD8 + T cell density, whereas negative HLA class I expression was correlated with low CD8 + T cell density at the invasive front. These results suggest that it is easier for CD8 + T cells to recognize presented peptides in the case of high HLA class Ⅰ expression at the tumor invasive front and could be a prognostic factor for OSCC. K E Y W O R D SHLA class Ⅰ, oral squamous cell carcinoma, prognostic factor, survival, tumor-infiltrating lymphocyte

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“…STAD is a highly heterogeneous cancer, and tumor heterogeneity is instrumental in immune evasion [24][25][26][27][28] . In fact, several studies have shown that tumor infiltrating immune cells are prognostic markers for cancer progression [29][30][31] . Therefore, we hypothesized that VGLL3 expression is associated with immune infiltration in STAD tumors, and a potential marker of the tumor immune microenvironment.…”

Section: Discussionmentioning

confidence: 99%

VGLL3 is a prognostic biomarker and correlated with clinical pathologic features and immune infiltrates in stomach adenocarcinoma

Zhang

Mao

et al. 2020

Sci Rep

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Due to its poor clinical outcome, there is an urgent need to identify novel prognostic markers for stomach adenocarcinoma (STAD). Here, we aimed to explore the relationship between VGLL3 expression and clinico-pathological features, dendritic cells, macrophages, and prognosis of STAD. VGLL3 expression levels were significantly associated with histological grade, T stage, and TNM stage. VGLL3 levels and patient's age were also independent prognostic factors of the clinical outcome of STAD. In addition, VGLL3 was associated with the abundance of macrophages and dendritic cells in tumor infiltrates, of which only VGLL3 and macrophage counts were the independent prognostic factors of immune cell infiltration in the TIMER Database. Extracellular matrix receptor interaction, focal adhesion, pathways in cancer, MAPK, JAK STAT, and WNT signaling pathways were enriched in VGLL3 high-expressing datasets as determined by Gene Set Enrichment Analysis (GSEA), while DNA replication, glyoxylate, and dicarboxylate metabolism, glutathione metabolism, homologous recombination, and glycosylphosphatidylinositol gpi banchor biosynthesis were enriched in VGLL3 low-expressing datasets. Thus, VGLL3 is a novel prognostic biomarker of both the clinical outcome and immune infiltration in STAD, and may therefore be a promising therapeutic target.Despite advances in treatment modalities, gastric cancer remains the most common cause of cancer-related deaths in Asia, and the second most common cause of death worldwide 1 . Around 90% to 95% of gastric cancer cases involve stomach adenocarcinomas (STAD) 2 . Although the survival of STAD patients has greatly improved in the past 20 years due to surgery, chemotherapy and targeted therapy, the prognosis is still unsatisfactory 3 . Poor differentiation, late diagnosis, lack of predictive markers, and ineffective therapeutic targets are key factors that drive STAD metastasis and recurrence 4 . Therefore, it is essential to explore the molecular mechanisms underlying STAD development and progression to identify novel prognostic biomarkers and potential therapeutic targets to treat gastric cancer.Transcription cofactor vestigial-like protein 3 (VGLL3) is a coactivator of mammalian toxicity equivalency factors (TEFs), and was associated with breast cancer, colon cancer, and lung cancer among other malignancies 5-9 . In our previous study, we found that VGLL3 at the protein level as determined by immunohistochemistry (IHC) was a novel prognostic biomarker for gastric cancer in the Chinese population 10 . However, its role at the mRNA level of STAD and immune microenvironment remains to be elucidated. To determine whether VGLL3 was involved in the progression of STAD, the Wilcox test and Kruskal test method were used to analyze the differences in VGLL3 expression in subgroups of clinic-pathological trait. Cox regression and log-rank test were used to evaluate significance of VGLL3 on disease prognosis.Recently, more and more evidence showed immune cell infiltration plays a vital role in predicting overall...

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Tumor‐infiltrating CD8⁺ T‐cell density is an independent prognostic marker for oral squamous cell carcinoma

Cited by 124 publications

References 42 publications

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

Prognostic value of HLA class I expression in patients with oral squamous cell carcinoma

VGLL3 is a prognostic biomarker and correlated with clinical pathologic features and immune infiltrates in stomach adenocarcinoma

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Tumor‐infiltrating CD8+ T‐cell density is an independent prognostic marker for oral squamous cell carcinoma

Cited by 124 publications

References 42 publications

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

Prognostic value of HLA class I expression in patients with oral squamous cell carcinoma

VGLL3 is a prognostic biomarker and correlated with clinical pathologic features and immune infiltrates in stomach adenocarcinoma

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Tumor‐infiltrating CD8⁺ T‐cell density is an independent prognostic marker for oral squamous cell carcinoma