Intratumoural-infiltrating CD4 + and FOXP3 + T cells as strong positive predictive markers for the prognosis of resectable colorectal cancer

Kuwahara, Taishi; Hazama, Shoichi; Suzuki, Nobuaki; Yoshida, Shigeo; Tomochika, Shinobu; Nakagami, Yuki; Matsui, Hiroto; Shindo, Yoshitaro; Kanekiyo, Shinsuke; Tokumitsu, Yukio; Iida, Michihisa; Tsunedomi, Ryouichi; Takeda, Shigeru; Yoshino, Shigefumi; Okayama, Naoko; Suehiro, Yutaka; Yamasaki, Takahiro; Fujita, Toshio; Kawakami, Yutaka; Ueno, Takayoshi; Nagano, Hiroaki

doi:10.1038/s41416-019-0559-6

Cited by 92 publications

(87 citation statements)

References 45 publications

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“…In contrast, the tumor infiltration of CD4 + and FOXP3 + TILs were reported as a favorable prognostic factor in CRC. 5 The rationale behind this prognostic divergence remains unclear, but it could be due to the functional discrepancy in CD4 + TILs within various tumors. These data justify the significant role of CD4 + TILs in controlling immune system to fight against malignancy.…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression of tumor-infiltrating CD4 ⁺ T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis

et al. 2020

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Tumor-infiltrating lymphocytes (TILs) play indispensable roles in the progression and response to treatment of solid tumors. However, the prognostic significance of CD4 + TILs is not fully disclosed in cancers generally and in CRC in particular, mainly due to the existence of different functional subsets of CD4 + T cells. We performed transcriptomic profiling of CD4 + TILs isolated from CRC patients in order to identify differentially expressed genes and their functional pathways in early versus advanced disease stages. We found that in advanced stages, genes related to immune and inflammatory responses, in particular Th1mediated immune response and cytotoxicity-mediated genes, were downregulated; while epigeneticmediated silencing genes were upregulated. Interestingly, we identified genes, which were steadily upregulated or downregulated in CD4 + TILs with CRC progression from stage I to IV. Additionally, of the top 200 deregulated genes, 43 upregulated and 64 downregulated genes showed similar deregulation trends in the cancer genome atlas CRC dataset. From these 97 deregulated genes, we identified a "poor prognosis CD4 gene signature (ppCD4sig)". Patients with high ppCD4sig score showed shorter diseasespecific survival (DSS) and progression-free interval (PFI). The ppCD4sig was an independent prognostic indicator for DSS (HR = 1.73, 95% CI 1.32-2.27, P = 0.0001) and PFI (HR = 1.75, 95% CI 1.3-2.35, P = 0.0016). Additionally, patients at advanced stages and at a younger age (<55 years) were more likely to have a high ppCD4sig score. Altogether, our data provide novel insights and a unique prognostic gene signature of CD4 + TILs in the CRC microenvironment.

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Section: Discussionmentioning

confidence: 99%

Differential gene expression of tumor-infiltrating CD4 ⁺ T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis

et al. 2020

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“…Cancer progression is determined not only by the malignant behavior of tumors but also by the immune microenvironment. In recent years, immune cell markers such as CD8+, CD163+, PD-L1+, and FOXP3 have shown prognostic impacts in patients suffering from solid tumors including NSCLC ( 9 , 10 , 20 ). However, a single immune feature cannot reflect the overall immune status of patients ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

Multiple Immune Features-Based Signature for Predicting Recurrence and Survival of Inoperable LA-NSCLC Patients

Guo

et al. 2020

Front. Oncol.

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Introduction The immune status of the tumor microenvironment is extremely complex. One single immune feature cannot reflect the integral immune status, and its prognostic value was limited. We postulated that the immune signature based on multiple immuno-features could markedly improve the prediction of post-chemoradiotherapeutic survival in inoperable locally advanced non-small-cell lung cancer (LA-NSCLC) patients. Methods In this study, 100 patients who were diagnosed as having inoperable LA-NSCLC between January 2005 and January 2016 were analyzed. A five immune features-based signature was then constructed using the nested repeat 10-fold cross validation with least absolute shrinkage and selection operator (LASSO) Cox regression model. Nomograms were then established for predicting prognosis. Results The immune signature combining five immuno-features was significantly associated with overall survival (OS) and progression-free survival (PFS) ( P = 0.002 and P = 0.014, respectively) in patients with inoperable LA-NSCLC, and at a cutoff of −0.05 stratified patients into two groups with 5-year OS rates of 39.8 and 8.8%, and 2-year PFS rates of 22.2 and 5.5% for the high- and low-immune signature groups, respectively. Integrating immune signature, we proposed predictive nomograms that were better than the traditional TNM staging system in terms of discriminating ability (OS: 0.692 vs. 0.588; PFS: 0.672 vs. 0.586, respectively) or net weight classification (OS: 32.96%; PFS: 9.22%), suggesting that the immune signature plays a significant role in improving the prognostic value. Conclusion Multiple immune features-based immune signature could effectively predict recurrence and survival of inoperable LA-NSCLC patients and complemented the prognostic value of the TNM staging system.

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“…Noteworthy, digital analysis via area stain performed far better than cell-count and visual analysis. Kuwahara et al is the only other group to have study intratumoral-in ltrating CD4 positive cells in colorectal carcinoma and found them to be among the strongest prognostic indicators 47 . However, metastasized colorectal cancer has not been included in this study.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of tumor-infiltrating immune cells in primary colorectal cancer and metastases

Martin

Tagscherer

Deckert

et al. 2020

Preprint

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Background Precise prognostic biomarkers are urgently needed to improve treatment and hence prognosis for patients with metastasized colorectal carcinoma. Tumor-infiltrating CD3 and CD8 positive lymphocytes have been shown to robustly predict survival of colorectal cancer in stages I-III in retro- and prospective studies. Their clinical value in metastasized tumors or the role of other types of immune cells is not well known. Methods We performed a detailed characterization of tumor infiltrating immune cells of primary colorectal cancer and metastases of 55 patients. Immune infiltrates were assessed visually and digitally. Results High densities of CD3, CD8, CD20, CD4, CD45R0, CD68, FOXP3, PD1 and PD-L1- positive cells in both primary colorectal cancer and metastases were significantly associated with prolonged survival in univariate and multivariate analysis. For CD3-CD8 immunoscore, CD8-CD20 TB cell score, CD45R0, CD68 and PD1 the evaluation of metastatic immune infiltrates showed superior hazard ratios, compared to evaluation of primary tumor-infiltrating immune cells (hazard ratio = 9.2; 5.7; 8.9; 5.7; 6.0, respectively). In case of FOXP3, CD4 and PD-L1 the combined evaluation of primary and metastatic immune infiltrates increased prognostic precision even further (hazard ratio = 5.7; 19.6 and 8.5, respectively). Visual analysis confirmed digital image analysis, but showed inferior hazard ratios. Conclusions A broad range of types of immune infiltrates predicts longer survival in metastasized colorectal cancer patients. Of all immune infiltrates, CD4 showed the highest prognostic precision. The combined assessment in primary colorectal cancer and metastases is valuable in most cases. Thus, automated digital analysis of immune infiltrates in colorectal metastases could improve the prognostic stratification of patients.

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Intratumoural-infiltrating CD4 + and FOXP3 + T cells as strong positive predictive markers for the prognosis of resectable colorectal cancer

Cited by 92 publications

References 45 publications

Differential gene expression of tumor-infiltrating CD4 ⁺ T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis

Differential gene expression of tumor-infiltrating CD4 ⁺ T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis

Multiple Immune Features-Based Signature for Predicting Recurrence and Survival of Inoperable LA-NSCLC Patients

Prognostic value of tumor-infiltrating immune cells in primary colorectal cancer and metastases

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Intratumoural-infiltrating CD4 + and FOXP3 + T cells as strong positive predictive markers for the prognosis of resectable colorectal cancer

Cited by 92 publications

References 45 publications

Differential gene expression of tumor-infiltrating CD4 + T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis

Differential gene expression of tumor-infiltrating CD4 + T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis

Multiple Immune Features-Based Signature for Predicting Recurrence and Survival of Inoperable LA-NSCLC Patients

Prognostic value of tumor-infiltrating immune cells in primary colorectal cancer and metastases

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Differential gene expression of tumor-infiltrating CD4 ⁺ T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis

Differential gene expression of tumor-infiltrating CD4 ⁺ T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis