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T cell factor 1 (TCF-1) is a transcription factor (TF) of the canonical Wnt signaling pathway that encoded by the Tcf7. The crucial role of TCF-1 in T cell development and memory formation has been widely recognized. Recent studies have demonstrated that exhausted CD8+ T cell with the expression of TCF-1 may have inspiring function to amplify immunoreaction and improve the response to immunotherapy in chronic viral infection and cancer. In this short review, we summarized recent progress in intratumoral exhausted CD8+ T cells expressing TCF-1 that represent a fantastic subset with stem cell-like properties that associated with improved antitumor immunity and response to immune checkpoint blockade (ICB).

Increasing evidence has revealed a significant association between microorganisms and oral squamous cell carcinoma (OSCC). Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, is considered an important potential etiologic agent of OSCC, but the underlying immune mechanisms through which P. gingivalis mediates tumor progression of the oral cancer remain poorly understood. Our cohort study showed that the localization of P. gingivalis in tumor tissues was related to poor survival of patients with OSCC. Moreover, P. gingivalis infection increased oral lesion multiplicity and size and promoted tumor progression in a 4-nitroquinoline-1 oxide (4NQO)–induced carcinogenesis mouse model by invading the oral lesions. In addition, CD11b+ myeloid cells and myeloid-derived suppressor cells (MDSCs) showed increased infiltration of oral lesions. Furthermore, in vitro observations showed that MDSCs accumulated when human-derived dysplastic oral keratinocytes (DOKs) were exposed to P. gingivalis, and CXCL2, CCL2, interleukin (IL)–6, and IL-8 may be potential candidate genes that facilitate the recruitment of MDSCs. Taken together, our findings suggest that P. gingivalis promotes tumor progression by generating a cancer-promoting microenvironment, indicating a close relationship among P. gingivalis, tumor progression of the oral cancer, and immune responses.

This study aimed to clarify the dynamic changes of exhaustion features in T cells during oral carcinogenesis.Mice were randomly divided into 4NQO group and control group. The exhaustion features of CD4The proportion of naive T cells in 4NQO group was lower than those in control group, while the proportion of effector memory T cells was higher in 4NQO group. The expression of inhibitory receptors on CD4T-cell dysfunction was established at the early premalignant phase of oral carcinogenesis; PD-1 blockade at the early premalignant phase can effectively reverse T-cell exhaustion features and then prevent carcinogenesis progression.

The heterogeneity of exhausted T cells (Tex) is a critical determinant of immune checkpoint blockade therapy efficacy. However, few studies have explored exhausted T cell subpopulations in human cancers. In the present study, we examined samples from two cohorts of 175 patients with head and neck squamous cell cancer (HNSCC) by multiplex immunohistochemistry (mIHC) to investigate two subsets of Tex, CD8+PD1+TCF1+ progenitor exhausted T cells (TCF1+Texprog) and CD8+PD1+TCF1− terminally exhausted T cells (TCF1−Texterm). Moreover, fresh tumor samples from 34 patients with HNSCC were examined by flow cytometry and immunohistochemistry to further investigate their properties and cytotoxic capabilities and their correlation with regulatory T cells (Tregs) in the tumor immune microenvironment (TIME). mIHC and flow cytometry analysis showed that TCF1−Texterm represented a greater proportion of CD8+PD1+Tex than TCF1+Texprog in most patients. TCF1+Texprog produced abundant TNFα, while TCF1−Texterm expressed higher levels of CD103, TIM-3, CTLA-4, and TIGIT. TCF1−Texterm exhibited a polyfunctional TNFα+GZMB+IFNγ+ phenotype; and were associated with better overall survival and recurrence-free survival. The results also indicated that larger proportions of TCF1−Texterm were accompanied by an increase in the proportion of Tregs. Therefore, it was concluded that TCF1−Texterm was the major CD8+PD1+Tex subset in the HNSCC TIME and that these cells favor patient survival. A high proportion of TCF1−Texterm was associated with greater Treg abundance.

Characterization of the dynamic change in the immunological landscape during malignant transformation from precancerous lesions to cancerous lesions in squamous cell carcinoma (SCC) is critical for the application of immunotherapy. Here, we performed single-cell RNA-Seq (scRNA-Seq) of 131,702 cells from 13 cancerous tissues of oral squamous cell carcinoma (OSCC), 3 samples of precancerous oral leukoplakia, and 8 adjacent normal samples. We found that tumor-infiltrating CD4+ and CD8+ T cells were functionally inhibited by immunosuppressive ligands expressed on various types of myeloid cells or neutrophils in the process of oral carcinogenesis. Notably, we identified a subset of myofibroblasts that exclusively expressed tryptophan 2,3-dioxygenase (TDO2). These TDO2+ myofibroblasts were located distally from tumor nests, and both CD4+ and CD8+ T cells were enriched around them. Functional experiments revealed that TDO2+ myofibroblasts were more likely to possess the ability for chemotaxis toward T cells but induced the transformation of CD4+ T cells into Tregs and caused CD8+ T cell dysfunction. We further showed that use of the TDO2 inhibitor LM10 attenuated the inhibitory states of T cells, restored the T cell antitumor response, and prevented the progression of OSCC malignant transformation in murine models. Our study reveals a multistep transcriptomic landscape of OSCC and demonstrates that TDO2+ myofibroblasts are potential targets for immunotherapy.

Background: The oral microbial ecosystem, with distinct characteristics in structure and evolution, plays an important role in the mucosal homeostasis. The characterization of baseline microbial and functional diversity in the oral microbiome has been discussed, yet the taxon-taxon relationships, and the role of the microbes themselves to the host mucosa are still lack of discussing. In addition, the current literature seems insufficient to draw a definitive conclusion about a possible impact of ageing on the oral microbiota. Therefore, the study focuses on the spatial and temporal characteristics of the oral microbial ecosystem, and its correlation with immune cell in oral homeostasis. Results: The V3V4 region of 16S rRNA gene of 30 samples from different sites (gingiva, palate, buccal, tongue) and life stages (adult, old) was analyzed. Flow cytometry was used to investigate the residing immune cells. The niche-specialist and age-related communities, characterized by alterations in microbiota structure, taxon-taxon relationship, microbial functions, and immune cell inhabiting, have been addressed. Interestingly, network analysis shows more antagonistic interactions in gingiva, palatal site, and old mice saliva, where harbor a richer diversity. While in buccal mucosa and tongue, it appears more synergic interactions to maintain the ecosystem balance. Functional analysis reveals that the significant factor that determines the niche for a microbe is its local habitat in the content of one specific age, which includes its immediate neighbors. Correlation analysis suggests strong associations between distinct oral bacteria and Th cells exist in different life stages. Conclusions: Our findings propose that the oral microbial ecosystem, with niche-specialist and age-related characteristics, has unique evolution and co-evolution with the host to maintain oral homeostasis, which provides critical insights on mucosal microbiology.

The heterogeneity of exhausted T cells (Tex) is a critical determinant of immune checkpoint blockade therapy efficacy. However, few studies have explored exhausted T cell subpopulations in human cancers. In the present study, we examined samples from two cohorts of 175 patients with head and neck squamous cell cancer (HNSCC) by multiplex immunohistochemistry (mIHC) to investigate two subsets of Tex, CD8

T cell factor 1 (TCF-1) is a transcription factor (TF) of the canonical Wnt signaling pathway that encoded by the Tcf7. The crucial role of TCF-1 in T cell development and memory formation has been widely recognized. Recent studies have demonstrated that exhausted CD8

Objective This study was aimed to analyze the role of T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT) expression on T cells in patients with oral squamous cell carcinoma (OSCC). Materials and methods Peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TILs) were collected from OSCC patients. The correlation between TIGIT expression and clinicopathologic features was analyzed by chi-square test. Phenotypic and functional study of TIGIT+ T cells were performed by flow cytometry. Results TIGIT was highly expressed on T cells from PBMC and TILs. High expression of TIGIT on CD4+ T cells (19.0%) and CD8+ T cells (35.9%) was also associated with higher T stage and nodal invasion. Moreover, TIGIT+ CD4+ and TIGIT+ CD8+ T cells sorted from OSCC patients showed a dysfunctional phenotype (low cell proliferation and low secretion of IL-2, TNF-α and IFN-γ), and TIGIT+ CD4+ T cells exhibited inhibitory function (high expression of Foxp3 and high amounts of IL-10). Importantly, TIGIT blockade can enhance the proliferation ability and effective cytokine production (IL-2, TNF-α, and IFN-γ) of CD4+ and CD8+ T cells from OSCC patients in vitro. Conclusions TIGIT-expressing T cells exhibit a lower effector cytokine-releasing phenotype in OSCC patients.

γδ T cells are a small subset of unconventional T cells that are enriched in the mucosal areas, and are responsible for pathogen clearance and maintaining integrity. However, the role of γδ T cells in head and neck squamous cell carcinoma (HNSCC) is largely unknown. Here, by using RNA-seq data from The Cancer Genome Atlas (TCGA), we discovered that HNSCC patients with higher levels of γδ T cells were positively associated with lower clinical stages and better overall survival, and high abundance of γδ T cells was positively correlated with CD8+/CD4+ T cell infiltration. Gene ontology and pathway analyses showed that genes associated with T cell activation, proliferation, effector functions, cytotoxicity, and chemokine production were enriched in the group with a higher γδ T cell abundance. Furthermore, we found that the abundance of γδ T cells was positively associated with the expression of the butyrophilin (BTN) family proteins BTN3A1/BTN3A2/BTN3A3 and BTN2A1, but only MICB, one of the ligands of NKG2D, was involved in the activation of γδ T cells, indicating that the BTN family proteins might be involved in the activation and proliferation of γδ T cells in the tumor microenvironment of HNSCC. Our results indicated that γδ T cells, along with their ligands, are promising targets in HNSCC with great prognostic values and treatment potentials.

Tertiary lymphoid structures (TLS) are ectopic lymphoid structures in cancers that are largely associated with favourable prognosis. However, the prognostic value of TLSs in oral squamous cell carcinoma (OSCC) is largely unknown, and the association between tumour infiltrating lymphocytes (TILs) and TLSs has been rarely explored in OSCC. In this study, associated markers of TLS, including peripheral node address (PNAd) in high endothelial venules, CD20 in B cells and CD3 in T cells, were examined in 168 OSCC patients, and survival analysis was performed between TLS-positive and TLS-negative cohorts. We detected the presence of TILs by staining CD8+ cytotoxic T cells and CD57+ NK cells as well. TLSs appeared as highly organized structures in 45 (26.8%) cases. TLS-positive patients had a better 5-year overall survival (OS) rate (88.9% vs. 56.1%, P P = 0.002). Moreover, the presence of TLS was an independent prognostic factor for both the 5-year OS rate (hazard ratio [HR] = 3.784; 95% confidence interval [CI], 1.498–9.562) and RFS rate (HR = 3.296; 95% CI, 1.279–8.490) in multivariate analysis. Furthermore, a higher density of CD8+ T cells and CD57+ NK cells was found in TLS-positive sections than in TLS-negative counterparts (P

Table S1. Immunohistochemical analysis of the expression of PD-1, PD-L1 and CD3 in oral lesions. Table S2. Immunohistochemical analysis of the expression of Foxp3, TIM-3 in oral lesions. (DOCX 15 kb)

Figure S2. The expression of TIM-3 in Tcm and Tem cells in draining lymph nodes and spleen. (A) The expression of TIM-3 on CD4+/CD8+ Tem cells between PD-1R group and PD-1S groups were analyzed by flow cytometry. Representative flow cytometry dot plots show the analysis of TIM-3 expression on CD4+ and CD8+ Tcm cells(left). The expression level of TIM-3 in Tcm cells were higher in lymph nodes of PD-1R group(right). (B) The expression of TIM-3 on CD4+/CD8+ Tem cells between PD-1S group and PD-1R group was analyzed by flow cytometry. Representative flow cytometry dot plots show the analysis of TIM-3 expression on CD4+ and CD8+ Tem cells(left). The expression level of TIM-3 in CD8+ Tem cells were higher in lymph nodes of PD-1R group(right). All data represent the average ± SEM. Statistical significance was determined by Student’s t test, *P

Figure S1. Expression of Foxp3 and TIM-3 in the immune microenvironment of the tongue lesions. Representative immunohistochemically stained images of the tissue sections from the tongue. Foxp3 (A) and TIM-3 (B) staining were detected in the two groups. The expression of Foxp3 and TIM-3 in the PD-1R group were significantly higher than that in the PD-1S group, Pâ

Purpose: Multiple negative regulators restrict the ability of T cells to attack tumors. This work demonstrates the role of PI3K-interacting protein 1 (Pik3ip1) in restraining T-cell responses and antitumor immunity. Experimental Design: An anti-Pik3ip1 mAb was generated to identify the Pik3ip1 expression pattern of hematopoietic cells. Pik3ip1−/− mice and a Pik3ip1 fusion protein were generated to investigate the effect of Pik3ip1 on T-cell–mediated antitumor immunity in MC38 and B16-F10 tumor models. Immunoblotting and confocal microscopy were used to identify inhibitory effects of Pik3ip1 on T-cell receptor (TCR) signaling. Pik3ip1 expression was quantified, and its impact on T-cell function in human tumors was measured. Results: We demonstrated that Pik3ip1 was predominantly expressed on T cells and served as an essential rheostat for T-cell–mediated immunity. A Pik3ip1 genetic deficiency led to enhanced T-cell responsiveness upon immunization with a neoantigen. Pik3ip1−/− mice exhibited a marked increase in antitumor immunity and were resistant to tumor growth. Furthermore, Pik3ip1 extracellular domain fusion protein enhanced MC38 tumor growth was observed. Mechanistically, we found that Pik3ip1 inhibited TCR signaling by mediating the degradation of SLP76 through Pik3ip1 oligomerization via its extracellular region. Consistent with the results from the mouse models, PIK3IP1 expression correlated with T-cell dysfunction in human tumors. Conclusions: Our data reveal a critical role for Pik3ip1 as a novel inhibitory immune regulator of T-cell responses and provide a potential molecular target for cancer immunotherapy.

Chemokines and hyperlipidemia are involved in the mechanism of chronic allograft nephropathy (CAN). In this study, the mRNA expression of RANTES and its receptor CCR5 on peripheral blood mononuclear cells were measured in renal transplant recipients with hyperlipidemia, and the effect of simvastatin treatment observed to investigate the mechanism and prevention of CAN. Sixty recipients selected from 167 renal transplant recipients were divided into two groups: group A without hyperlipidemia (n = 30) and group B with hyperlipidemia (n = 30). The control group consisted of 30 healthy volunteers. The recipients in group B were treated with simvastatin for 3 months. We estimated serum lipid levels and mRNA expressions of RANTES and CCR5. The mRNA expressions of RANTES and CCR5 were significantly higher in renal transplant recipients compared with controls. The expressions were much higher in group B than in group A patients. In group B patients, serum lipid levels decreased dramatically after simvastatin treatment. Meanwhile, the mRNA expressions of RANTES and CCR5 were reduced significantly after 1.5 months of simvastatin treatment to a level significantly lower than that in group A after 3 months of treatment. The increased expressions of RANTES and CCR5 mRNAs in renal transplant recipients with hyperlipidemia might be involved in CAN due to hyperlipidemia. Simvastatin seemed to reduce the chemokine transcripts in renal recipients with hyperlipidemia.