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Helper T cell-dominant tertiary lymphoid structures are associated with disease relapse of advanced colorectal cancer.

ABSTRACT: Tertiary lymphoid structures (TLSs), clusters of immune cells found around tumor tissue, have been shown to be associated with anti-tumor immunity, but the cellular composition within each TLS and whether the cellular composition of a TLS affects a patient's prognosis are poorly understood. In the present study, each TLS was categorized according to its cellular composition determined by a system of multiplex immunohistochemical staining and quantitative analysis, and the correlation between the category and prognosis was examined. Sixty-seven patients with curatively resected stage II/III colorectal cancer (CRC) were enrolled. A TLS, consisting of germinal center B cells, follicular dendritic cells, T helper (Th) cells, B cells, cytotoxic T cells, and macrophages, was confirmed in the tumor tissue of 58 patients (87%). The densities of Th cells and macrophages were significantly higher in relapsed patients than in not-relapsed patients (p = .043 and p = .0076). A higher ratio of Th cells was the most significant independent risk factor for disease relapse on multivariate analysis. The subset increasing in Th cells was GATA3⁺ Th2. A total of 353 TLSs was divided into five clusters according to immune cell composition. Among them, the Th-rich type TLS was significantly increased (p = .0009) in relapsed patients. These data suggest the possibility that Th cell-dominant composition might disturb the anti-tumor immune response, and the function of each TLS might differ depending on its composition.

SUBMITTER: Yamaguchi K

PROVIDER: S-EPMC7028340 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Helper T cell-dominant tertiary lymphoid structures are associated with disease relapse of advanced colorectal cancer.

Yamaguchi Kyoko K Ito Mamoru M Ohmura Hirofumi H Hanamura Fumiyasu F Nakano Michitaka M Tsuchihashi Kenji K Nagai Shuntaro S Ariyama Hiroshi H Kusaba Hitoshi H Yamamoto Hidetaka H Oda Yoshinao Y Nakamura Masafumi M Akashi Koichi K Baba Eishi E

Oncoimmunology 20200217 1

Tertiary lymphoid structures (TLSs), clusters of immune cells found around tumor tissue, have been shown to be associated with anti-tumor immunity, but the cellular composition within each TLS and whether the cellular composition of a TLS affects a patient's prognosis are poorly understood. In the present study, each TLS was categorized according to its cellular composition determined by a system of multiplex immunohistochemical staining and quantitative analysis, and the correlation between the ...[more]

PMID: 32117589

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Project description:IntroductionTertiary Lymphoid Structures (TLS) in cancer tissue are potential sites for the organisation of immune responses to cancer, and correlate positively with improved clinical outcomes for patients including in colorectal cancer (CRC). However it has proven challenging to standardise assessment of TLS due to the highly variable appearances of circumscribed domains of TLS within tissue sections. A recent three-dimensional reconstruction of TLS in CRC tissue showed that TLS are often large, multi-lobular structures, suggesting that assessing TLS across whole sections may be necessary to provide an accurate view of TLS activity in a patient's tumour.MethodsWe used whole-section scans of multiplexed immunofluorescence images to characterise TLS from 22 subjects with CRC. Multiplexed staining for CD20, CD3, CD8, Foxp3 and Ki-67 enabled us to identify B-cells, CD8+ T-cells, Foxp3- CD4 T-cells, and Foxp3+ CD4 Tcells in all sections, and quantify both the presence of these cell subsets in lymphocytic clusters and their degree of proliferation within those clusters.ResultsIn total we identified 524 lymphocytic clusters with morphology consistent with TLS. TLS domains varied substantially between samples in size, morphology, cellular constituents, count (from 4 to 100), and proportion of total section area they occupied (0.2%-7.8%). We quantified proliferation of B-cells and T-cell subsets within TLS domains across entire sections and compared data to the canonical approach of counting and phenotyping individual TLS domains. The whole-slide approach proved simpler, generating digital summaries that readily identified patients with strikingly different levels of immune activity within their TLS. Strong correlations were observed between the proliferation of B-cells and T-cell subsets. The presence of non-proliferating Foxp3+ CD4 T-cells within TLS showed no correlation with the level of proliferation of other lymphocyte subsets.DiscussionWhole-section digital quantification of immune cell activity within TLS has advantages over canonical approaches, and could accelerate research into correlations between TLS status and clinical outcomes, with potential to enable a standardised assay for clinical use.

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Helper T cell-dominant tertiary lymphoid structures are associated with disease relapse of advanced colorectal cancer.

Publications

Helper T cell-dominant tertiary lymphoid structures are associated with disease relapse of advanced colorectal cancer.

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