Dataset Information

TCR sequencing analysis of cancer tissues and tumor draining lymph nodes in colorectal cancer patients.

ABSTRACT: Tumor draining lymph nodes (TDLNs) are located in the routes of lymphatic drainage from a primary tumor and have the highest risk of metastasis in various types of solid tumors. TDLNs are also considered as a tissue to activate the antitumor immunity, where antigen-specific effector T cells are generated. However, T cell receptor (TCR) repertoires in TDLNs have not been well characterized. We collected 23 colorectal cancer tumors with 203 lymph nodes with/without metastatic cancer cells (67 were metastasis-positive and the remaining 136 were metastasis-negative) and performed TCR sequencing. Metastasis-positive TDLNs showed a significantly lower TCR diversity and shared TCR clonotypes more frequently with primary tumor tissues compared to metastasis-negative TDLNs. Principal component analysis indicated that TDLNs with metastasis showed similar TCR repertoires. These findings suggest that cancer-reactive T cell clones could be enriched in the metastasis-positive TDLNs.

SUBMITTER: Matsuda T

PROVIDER: S-EPMC6492974 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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TCR sequencing analysis of cancer tissues and tumor draining lymph nodes in colorectal cancer patients.

Matsuda Tatsuo T Miyauchi Eisaku E Hsu Yu-Wen YW Nagayama Satoshi S Kiyotani Kazuma K Zewde Makda M Park Jae-Hyun JH Kato Taigo T Harada Makiko M Matsui Shimpei S Ueno Masashi M Fukuda Kazumasa K Suzuki Nobuaki N Hazama Shoichi S Nagano Hiroaki H Takeuchi Hiroya H Vigneswaran Wickii T WT Kitagawa Yuko Y Nakamura Yusuke Y

Oncoimmunology 20190322 6

Tumor draining lymph nodes (TDLNs) are located in the routes of lymphatic drainage from a primary tumor and have the highest risk of metastasis in various types of solid tumors. TDLNs are also considered as a tissue to activate the antitumor immunity, where antigen-specific effector T cells are generated. However, T cell receptor (TCR) repertoires in TDLNs have not been well characterized. We collected 23 colorectal cancer tumors with 203 lymph nodes with/without metastatic cancer cells (67 were ...[more]

PMID: 31069156

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Project description:BackgroundDendritic cells (DCs) are important mediators of anti-tumor immune responses. We hypothesized that an in-depth analysis of dendritic cells and their spatial relationships to each other as well as to other immune cells within tumor draining lymph nodes (TDLNs) could provide a better understanding of immune function and dysregulation in cancer.MethodsWe analyzed immune cells within TDLNs from 59 breast cancer patients with at least 5 years of clinical follow-up using immunohistochemical staining with a novel quantitative image analysis system. We developed algorithms to analyze spatial distribution patterns of immune cells in cancer versus healthy intra-mammary lymph nodes (HLNs) to derive information about possible mechanisms underlying immune-dysregulation in breast cancer. We used the non-parametric Mann-Whitney test for inter-group comparisons, Wilcoxon Matched-Pairs Signed Ranks test for intra-group comparisons and log-rank (Mantel-Cox) test for Kaplan Maier analyses.ResultsDegree of clustering of DCs (in terms of spatial proximity of the cells to each other) was reduced in TDLNs compared to HLNs. While there were more numerous DC clusters in TDLNs compared to HLNs,DC clusters within TDLNs tended to have fewer member DCs and also consisted of fewer cells displaying the DC maturity marker CD83. The average number of T cells within a standardized radius of a clustered DC was increased compared to that of an unclustered DC, suggesting that DC clustering was associated with T cell interaction. Furthermore, the number of T cells within the radius of a clustered DC was reduced in tumor-positive TDLNs compared to HLNs. Importantly, clinical outcome analysis revealed that DC clustering in tumor-positive TDLNs correlated with the duration of disease-free survival in breast cancer patients.ConclusionsThese findings are the first to describe the spatial organization of DCs within TDLNs and their association with survival outcome. In addition, we characterized specific changes in number, size, maturity, and T cell co-localization of such clusters. Strategies to enhance DC function in-vivo, including maturation and clustering, may provide additional tools for developing more efficacious DC cancer vaccines.

Project description:Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.

Dataset Information

TCR sequencing analysis of cancer tissues and tumor draining lymph nodes in colorectal cancer patients.

Publications

TCR sequencing analysis of cancer tissues and tumor draining lymph nodes in colorectal cancer patients.

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