Human T cells interacting with HNSCC‐derived mesenchymal stromal cells acquire tissue‐resident memory like properties

Mazzoni, Alessio; Maggi, Laura; Montaini, Gianni; Ramazzotti, Matteo; Capone, Manuela; Vanni, Anna; Locatello, Luca Giovanni; Barra, G.; Palma, Raffaele De; Gallo, Oreste; Cosmi, Lorenzo; Liotta, Francesco; Annunziato, Francesco

doi:10.1002/eji.202048544

Cited by 12 publications

(8 citation statements)

References 25 publications

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“…CD8 + T RM cells contributed to local immune protection in early-stage HGSOC tumors. To explain how CD8 + T RM cells form in early-stage HGSOC tumors, we checked the expression of survival factors, such as IL15 , IL17 , and NOTCH ligands, which are known to determine T RM cell formation and persistence ( 35–37 ). One of them, IL15 was expressed in HGSOC-derived malignant epithelial cells and induced the formation of CD8 + T RM cells and CD8 + T EX cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer

Fang

Chen

et al. 2022

Clinical Cancer Research

104

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Purpose: The heterogeneity of high-grade serous ovarian cancer (HGSOC) is not well studied, which severely hinders clinical treatment of HGSOC. Thus, it is necessary to characterize the heterogeneity of HGSOC within its tumor microenvironment (TME). Experimental Design: The tumors of 7 treatment-naïve patients with HGSOC at early or late stages and five age-matched nonmalignant ovarian samples were analyzed by deep single-cell RNA sequencing (scRNA-seq). Results: A total of 59,324 single cells obtained from HGSOC and nonmalignant ovarian tissues were sequenced by scRNA-seq. Among those cells, tumor cells were characterized by a set of epithelial-to-mesenchymal transition (EMT)-associated gene signatures, in which a combination of NOTCH1, SNAI2, TGFBR1, and WNT11 was further selected as a genetic panel to predict the poor outcomes of patients with HGSOC. Matrix cancer-associated fibroblasts (mCAF) expressing α-SMA, vimentin, COL3A, COL10A, and MMP11 were the dominant CAFs in HGSOC tumors and could induce EMT properties of ovarian cancer cells in the coculture system. Specific immune cell subsets such as C7-APOBEC3A M1 macrophages, CD8+ TRM, and TEX cells were preferentially enriched in early-stage tumors. In addition, an immune coinhibitory receptor TIGIT was highly expressed on CD8+ TEX cells and TIGIT blockade could significantly reduce ovarian cancer tumor growth in mouse models. Conclusions: Our transcriptomic results analyzed by scRNA-seq delineate an ecosystemic landscape of HGSOC at early or late stages with a focus on its heterogeneity with TME. The major applications of our findings are a four–EMT gene model for prediction of HGSOC patient outcomes, mCAFs’ capability of enhancing ovarian cancer cell invasion and potential therapeutic value of anti-TIGIT treatment.

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Section: Resultsmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer

Fang

Chen

et al. 2022

Clinical Cancer Research

104

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“…From the analysis of our already published HNSCC-MSC transcriptome data [ 8 , 9 ] we observed that among the genes mostly upregulated by IFN-γ and TNF-α stimulation there were IDO1 and IL4I1 ( Figure 1 A). Upregulation of IDO1 was expected, given that its expression has already been described in HNSCC-MSC and its known dependency on IFN-γ signaling [ 7 ].…”

Section: Resultsmentioning

confidence: 98%

“…We have previously shown that MSC obtained from head–neck squamous cell carcinoma (HNSCC) inhibit T cell functions [ 7 ]. Moreover, we have shown that the transcriptional signature of HNSCC-MSC is strongly influenced by two cytokines commonly produced by anti-tumor T cells: IFN-γ and TNF-α [ 8 ]. In this study, we hypothesized that additional mechanism than IDO1 can be involved in the immunosuppressive activity of HNSCC-MSC.…”

Section: Introductionmentioning

confidence: 99%

IL4I1 Is Expressed by Head–Neck Cancer-Derived Mesenchymal Stromal Cells and Contributes to Suppress T Cell Proliferation

Mazzoni

Capone

Ramazzotti

et al. 2021

JCM

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Amino acids have a primary role in cancer metabolism. Beyond their primary biosynthetic role, they represent also an alternative fuel while their catabolites can influence the epigenetic control of gene expression and suppress anti-tumor immune responses. The accumulation of amino-acid derivatives in the tumor microenvironment depends not only on the activity of tumor cells, but also on stromal cells. In this study, we show that mesenchymal stromal cells derived from head–neck cancer express the amino acid oxidase IL4I1 that has been detected in different types of tumor cells. The catabolic products of IL4I1, H2O2, and kynurenines are known to suppress T cell response. We found that neutralization of IL4I1 activity can restore T cell proliferation. Thus, therapeutical strategies targeting enzymes involved in amino-acid catabolism may be helpful to contemporary block tumor cell migration and restore an efficacious anti-tumor immunity.

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“…Since the increase in PD-1 expression may be the result of T cell activation, PD-1 might remain upregulated in the context of a persistent antigen-specific immune stimulation. Furthermore, PD-1+ T cells include potentially tumor-specific T RM cells, exerting anti-neoplastic effects [ 43 ]. All these findings support the idea that PD-1 expression should not be merely considered as an exhaustion marker but rather a reflection of the antitumor reactivity, and suggest that patients with high expression of PD-1 on T cells could be potential candidates for anti-PD-1/PD-L1 blockade.…”

Section: Discussionmentioning

confidence: 99%

The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: a multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors

Tosi

Parisatto

Menegaldo

et al. 2022

J Exp Clin Cancer Res

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Background Immune checkpoint inhibitors (ICI) are approved for treatment of recurrent or metastatic oropharyngeal head and neck squamous cell carcinoma in the first- and second-line settings. However, only 15–20% of patients benefit from this treatment, a feature increasingly ascribed to the peculiar characteristics of the tumor immune microenvironment (TIME). Methods Immune-related gene expression profiling (GEP) and multiplex immunofluorescence (mIF) including spatial proximity analysis, were used to characterize the TIME of 39 treatment-naïve oropharyngeal squamous cell carcinomas (OPSCC) and the corresponding lymph node metastases. GEP and mIF results were correlated with disease-free survival (DFS). HPV-positive tumors disclosed a stronger activation of several immune signalling pathways, as well as a higher expression of genes related to total tumor-infiltrating lymphocytes, CD8 T cells, cytotoxic cells and exhausted CD8 cells, than HPV-negative patients. Accordingly, mIF revealed that HPV-positive lesions were heavily infiltrated as compared to HPV-negative counterparts, with a higher density of T cells and checkpoint molecules. CD8+ T cells appeared in closer proximity to tumor cells, CD163+ macrophages and FoxP3+ cells in HPV-positive primary tumors, and related metastases. In HPV-positive lesions, PD-L1 expression was increased as compared to HPV-negative samples, and PD-L1+ tumor cells and macrophages were closer to PD-1+ cytotoxic T lymphocytes. Considering the whole cohort, a positive correlation was observed between DFS and higher levels of activating immune signatures and T cell responses, higher density of PD-1+ T cells and their closer proximity to tumor cells or PD-L1+ macrophages. HPV-positive patients with higher infiltration of T cells and macrophages had a longer DFS, while CD163+ macrophages had a negative role in prognosis of HPV-negative patients. Conclusions Our results suggest that checkpoint expression may reflect an ongoing antitumor immune response. Thus, these observations provide the rationale for the incorporation of ICI in the loco-regional therapy strategies for patients with heavily infiltrated treatment-naïve OPSCC, and for the combination of ICI with tumor-specific T cell response inducers or TAM modulators for the “cold” OPSCC counterparts.

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Human T cells interacting with HNSCC‐derived mesenchymal stromal cells acquire tissue‐resident memory like properties

Cited by 12 publications

References 25 publications

Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer

Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer

IL4I1 Is Expressed by Head–Neck Cancer-Derived Mesenchymal Stromal Cells and Contributes to Suppress T Cell Proliferation

The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: a multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors

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