Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma

Lechner, Axel; Schlößer, Hans; Rothschild, Sacha I.; Thelen, Martin; Reuter, Sabrina; Zentis, Peter; Shimabukuro‐Vornhagen, Alexander; Theurich, Sebastian; Wennhold, Kerstin; García-Márquez, María; Tharun, Lars; Quaas, Alexander; Schauß, Astrid; Isensee, Jörg; Hucho, Tim; Huebbers, Christian U.; Bergwelt‐Baildon, Michael von; Beutner, Dirk

doi:10.18632/oncotarget.17901

Cited by 107 publications

(113 citation statements)

References 61 publications

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“…The composition of T cell subsets in HNSCC has been studied by different groups. 17,33,34 In contrast, knowledge about B cellular components of the TME in HNSCC is scarce. This study provides comprehensive data of tumor-associated B cell subsets in HNSCC and demonstrates different TAA gene expression patterns in HPV + and HPV − HNSCC patients.…”

Section: Discussionmentioning

confidence: 99%

“…42 Hence, despite high expression levels of CD86 on antigen-presenting B cells, activation of T cells might be substantially impaired in HNSCC microenvironment due to previously demonstrated high percentages of CTLA-4 expressing T cells in the TME. 33 The percentage of BAPC in HPV-driven tumors was decreased compared to HPV − HNSCC. This might be explained by higher mutational rate in HPV − HNSCC 43 and therefore increased immunogenicity and infiltration by antigen-presenting cells.…”

Section: Gene Expression (Hnscc Vs Non-cancerous Mucosa)mentioning

confidence: 97%

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Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma

et al. 2019

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B lymphocytes are important players in immune responses to cancer. However, their composition and function in head and neck squamous cell carcinoma (HNSCC) has not been well described. Here, we analyzed B cell subsets in HNSCC (n = 38), non-cancerous mucosa (n = 14) and peripheral blood from HNSCC patients (n = 38) and healthy controls (n = 20) by flow cytometry. Intratumoral B cells contained high percentages of activated (CD86+), antigen-presenting (CD86+/CD21−) and memory B cells (IgD−/CD27+). T follicular helper cells (CD4+/CXCR5+/CD45RA−/CCR7−) as key components of tertiary lymphoid structures and plasma cells made up high percentages of the lymphocyte infiltrate. Percentages of regulatory B cell varied depending on the regulatory phenotype. Analysis of humoral immune responses against 23 tumor-associated antigens (TAA) showed reactivity against at least one antigen in 56% of HNSCC patients. Reactivity was less frequent in human papillomavirus associated (HPV+) patients and healthy controls compared to HPV negative (HPV−) HNSCC. Likewise, patients with early stage HNSCC or MHC-I loss on tumor cells had low TAA responses. Patients with TAA responses showed CD4+ dominated T cell infiltration compared to mainly CD8+ T cells in tumors without detected TAA response. To summarize, our data demonstrates different immune infiltration patterns in relation to serological TAA response detection and the presence of B cell subpopulations in HNSCC that can engage in tumor promoting and antitumor activity. In view of increasing use of immunotherapeutic approaches, it will be important to include B cells into comprehensive phenotypic and functional analyses of tumor-associated lymphocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Gene Expression (Hnscc Vs Non-cancerous Mucosa)mentioning

confidence: 97%

Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma

et al. 2019

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“…Recent publications have shed light on tumor immunology and immune escape mechanisms in OSCC (26,27,(35)(36)(37)(38), but up-todate knowledge is fragmented and partially controversial. The main focus of our present study was therefore to further delineate the morphologic phenotype of the immunologic tumor-host interaction in OSCC as described in the cancer immunity cycle (15,20), in particular to exactly describe the composition of the inflammatory infiltrate involved in cell-mediated immunity, composed by various subsets of T cells (CD3 + T cells; CD4 + T cells; CD8 + T killer cells; CD4 + FOXP3 + Tregs; IL-17A + Th17 cells) and its association with HLA class I expression, IFN-g expression, and morphology, taking into account spatial heterogeneity of immunologic parameters (stroma versus epithelial infiltrate; IF versus TCe).…”

Section: Discussionmentioning

confidence: 99%

“…In OSCC, recent publications have shed light on immunologic TME and immune escape mechanisms (4,26,27,(35)(36)(37)(38), but knowledge is still fragmented. The association of composition of the immunologic TME, including TIL subsets with histomorphology and patient prognosis, remains to be elucidated, especially the prognostic influence of CD8 + and FOXP3 + TILs, which is currently a matter of debate with controversial results in published studies (reviewed in Refs.…”

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confidence: 99%

Composition and Clinical Impact of the Immunologic Tumor Microenvironment in Oral Squamous Cell Carcinoma

Boxberg

Leising

Steiger

et al. 2019

The Journal of Immunology

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Immunotherapy shows promising results and revolutionizes treatment of oral squamous cell carcinoma (OSCC). The immunologic microenvironment might have prognostic/predictive implications. Morphologic immunologic parameters (inflammatory infiltrate, stromal content, and budding activity [BA] [potentially indicating epithelial–mesenchymal transition]) were evaluated in 66 human primary therapy-naive OSCCs. Intraepithelial/stromal tumor-infiltrating lymphocytes (TILs; CD3+/CD4+/CD8+/CD4+FOXP3+/IL-17A+) were quantified, and ratios were calculated. HLA class I in tumor cells was evaluated immunohistochemically. mRNA in situ hybridization to detect IFN-γ was performed. Analysis was performed within invasive front (IF) and tumor center (TCe). Decreased HLA expression was associated with low TIL density, pronounced stromal content, and high BA; IFN-γ in TILs was correlated with high-density TILs; and IFN-γ in tumor cells was correlated with absence of BA (p < 0.05). Heterogeneity of parameters (TCe/IF) was rare. Low density of stromal CD4+FOXP3+ TILs within TCe and IF was identified as an independent prognostic factor for poor overall, disease-specific, and disease-free survival (p ≤ 0.011). Refining prognostication in OSCC with high-density CD4+FOXP3+ infiltrate within TCe and/or IF, high FOXP3:CD4 ratio was significantly correlated with favorable outcome in this subgroup. Furthermore, high-stromal CD8:CD4 ratio was found to be an independent favorable prognostic factor. In summary, immunologic parameters were closely intertwined. Morphologic correlates of epithelial–mesenchymal transition were associated with downregulation of HLA and decreased inflammation. Heterogeneity was infrequent. Low-density stromal CD4+FOXP3+ infiltrate within TCe and IF was an independent poor prognostic factor. Stratification of cases with high-density CD4+FOXP3+ TILs by FOXP3:CD4 ratio enables refinement of prognostication of this subgroup. CD8:CD4 ratio was identified as an independent prognostic factor.

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“…Further, the relative proportion of immune cell subsets and checkpoint molecule expression is similar between virus-positive and -negative tumors. 145 Finally, mutational burden has also been associated with response to immune checkpoint blockade, and HPV-negative tumors have a higher mutational burden when compared with their virus-positive counterparts.…”

Section: Head and Neck Squamous Cell Carcinomamentioning

confidence: 99%

Implications of the tumor immune microenvironment for staging and therapeutics

et al. 2018

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Characterizing the tumor immune microenvironment enables the identification of new prognostic and predictive biomarkers, the development of novel therapeutic targets and strategies, and the possibility to guide first-line treatment algorithms. Although the driving elements within the tumor microenvironment of individual primary organ sites differ, many of the salient features remain the same. The presence of a robust antitumor milieu characterized by an abundance of CD8+ cytotoxic T-cells, Th1 helper cells, and associated cytokines often indicates a degree of tumor containment by the immune system and can even lead to tumor elimination. Some of these features have been combined into an ‘Immunoscore’, which has been shown to complement the prognostic ability of the current TNM staging for early stage colorectal carcinomas. Features of the immune microenvironment are also potential therapeutic targets, and immune checkpoint inhibitors targeting the PD-1/ PD-L1 axis are especially promising. FDA-approved indications for anti-PD-1/PD-L1 are rapidly expanding across numerous tumor types and, in certain cases, are accompanied by companion or complimentary PD-L1 immunohistochemical diagnostics. Pathologists have direct visual access to tumor tissue and in-depth knowledge of the histological variations between and within tumor types and thus are poised to drive forward our understanding of the tumor microenvironment. This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load. Characteristics of the local immune contexture and current pathology-related practices for specific tumor types are also addressed. In the future, characterization of the host antitumor immune response using multiplexed and multimodality biomarkers may help predict which patients will respond to immune-based therapies.

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Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma

Cited by 107 publications

References 61 publications

Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma

Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma

Composition and Clinical Impact of the Immunologic Tumor Microenvironment in Oral Squamous Cell Carcinoma

Implications of the tumor immune microenvironment for staging and therapeutics

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