Immune Landscape of Colorectal Cancer Tumor Microenvironment from Different Primary Tumor Location

Zhang, Longhui; Zhao, Yuetao; Dai, Ying; Cheng, Jianan; Gong, Zhihua; Feng, Yi; Sun, Chengdu; Jia, Qingzhu; Zhu, Bo

doi:10.3389/fimmu.2018.01578

Cited by 145 publications

(121 citation statements)

References 55 publications

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“…The immune landscape of CRC TME comprises of diverse populations that modulate anti-tumor responses. We and others have previously shown accumulation of immunosuppressive myeloid cells and Treg expressing multiple IC in CRC TME [14][15][16]. Moreover, previous studies have reported TIM-3 expression on dysfunctional T cells in various malignancies [17].…”

Section: Cd4 + Tim-3 + T Cells In the Tumor Microenvironment Have Mormentioning

confidence: 79%

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4− (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3− counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.

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Section: Cd4 + Tim-3 + T Cells In the Tumor Microenvironment Have Mormentioning

confidence: 79%

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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“…Accumulating researches have highlighted the crucial role of cancer microenvironment in melanoma and CRC progression, metastasis and evasion of the immune surveillance . In this study, we found that the quantity of CAFs in melanoma and CRC were positively correlated with PD‐L1 expression.…”

Section: Discussionmentioning

confidence: 99%

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Zhou

Zhang

et al. 2019

Intl Journal of Cancer

152

131

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Cancer‐associated fibroblasts (CAFs) play a key role in orchestrating the tumor malignant biological properties within tumor microenvironment and evidences demonstrate that CAFs are a critical regulator of tumoral immunosuppression of the T cell response. However, the functions and regulation of CAFs in the expression of programmed death‐ligand 1 (PD‐L1) in melanoma and colorectal carcinoma (CRC) are not completely understood. Herein, by scrutinizing the expression of α‐SMA and PD‐L1 in melanoma and CRC tissues, we found that CAFs was positive correlated with PD‐L1 expression. Further analyses showed that CAFs promoted PD‐L1 expression in mice tumor cells. By detecting a majority of cytokines expression in normal mice fibroblasts and CAFs, we determined that CXCL5 was abnormal high expression in CAFs and the immunohistochemistry and in situ hybridization confirmed that were CAFs which were expressing CXCL5. In addition, CXCL5 promoted PD‐L1 expression in B16, CT26, A375 and HCT116. The silencing of CXCR2, the receptor of CXCL5, inhibited the PD‐L1 expression induced by CAFs in turn. Functionally, CXCL5 derived by CAFs promoted PD‐L1 expression in mice tumor cells through activating PI3K/AKT signaling. LY294002, the inhibitor of PI3K, confirmed that CXCL5 forested an immunosuppression microenvironment by promoting PD‐L1 expression via PI3K/AKT signaling. Meanwhile, the B16/CT26 xenograft tumor models were used and both CXCR2 and p‐AKT were found to be positively correlated with PD‐L1 in the xenograft tumor tissues. The immunosuppressive action of CAFs on tumor cells is probably reflective of them being a potential therapeutic biomarker for melanoma and CRC.

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“…To quantify the infiltration levels of stromal cells located in tumour microenvironment, the single-sample gene set enrichment analysis (ssGSEA) method was applied using the 'GSVA' package. 23 The marker genes of immune and stromal cells used for ssGSEA were retrieved from the works of Bindea et al 24…”

Section: Characterization Of Tumour Microenvironmentmentioning

confidence: 99%

A stroma‐related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early‐stage colon cancer

Zhou

Sun

Zheng

et al. 2020

J Cellular Molecular Medi

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The heterogeneity in prognoses and chemotherapeutic responses of colon cancer patients with similar clinical features emphasized the necessity for new biomarkers that help to improve the survival prediction and tailor therapies more rationally and precisely. In the present study, we established a stroma‐related lncRNA signature (SLS) based on 52 lncRNAs to comprehensively predict clinical outcome. The SLS model could not only distinguish patients with different recurrence and mortality risks through univariate analysis, but also served as an independent factor for relapse‐free and overall survival. Compared with the conventionally used TNM stage system, the SLS model clearly possessed higher predictive accuracy. Moreover, the SLS model also effectively screened chemotherapy‐responsive patients, as only patients in the low‐SLS group could benefit from adjuvant chemotherapy. The following cell infiltration and competing endogenous RNA (ceRNA) network functional analyses further confirmed the association between the SLS model and stromal activation‐related biological processes. Additionally, this study also identified three phenotypically distinct colon cancer subtypes that varied in clinical outcome and chemotherapy benefits. In conclusion, our SLS model may be a significant determinant of survival and chemotherapeutic decision‐making in colon cancer and may have a strong clinical transformation value.

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Immune Landscape of Colorectal Cancer Tumor Microenvironment from Different Primary Tumor Location

Cited by 145 publications

References 55 publications

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

A stroma‐related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early‐stage colon cancer

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