tumor-transplantation-for-assessing-dynamics-tumor-infiltrating-cd8-t

Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8<sup>+</sup> T Cells in Mice

T cell-mediated immunity plays a crucial role in immune responses against tumors, with cytotoxic T lymphocytes (CTLs) playing the leading role in ...

draining-lymph-node-metastasis-model-for-assessing-dynamics-antigen

Draining Lymph Node Metastasis Model for Assessing the Dynamics of Antigen-Specific CD8<sup>+</sup> T Cells During Tumorigenesis

Tumor antigen-specific CD8+ T cells from draining lymph nodes gain an accumulating importance in mounting anti-tumor immune response during tumorigenesis. ...

Third Military Medical University

The refractive indices, absorption coefficients, and complex dielectric constants of paraffin-embedded brain glioma and normal brain tissues have been measured by a terahertz time-domain spectroscopy (THz-TDS) system in the 0.2- to 2.0-THz range. The spectral differences between gliomas and normal brain tissues were obtained. Compared with normal brain tissue, our results indicate that paraffin-embedded brain gliomas have a higher refractive index, absorption coefficient, and dielectric constant. Based on these results, the best THz frequencies for different methods of paraffin-embedded brain glioma imaging, such as intensity imaging, coherent imaging with continuum THz sources, and THz pulsed imaging with short-pulsed THz sources, are analyzed.

Terahertz pulsed spectroscopy of paraffin-embedded brain glioma.

While myelin deficit of the central nervous system leads to several severe diseases, the definitive diagnostic means are lacking. We proposed and performed terahertz time-domain spectroscopy (THz-TDS) combined with chemometric techniques to discriminate and evaluate the severity of myelin deficit in mouse and rhesus monkey brains. The THz refractive index and absorption coefficient of paraffin-embedded brain tissues from both normal and mutant dysmyelinating mice are shown. Principal component analysis of time-domain THz signal (PCA-tdTHz) and absorption-refractive index relation of THz spectrum identified myelin deficit without exogenous labeling or any pretreatment. Further, with the established PCA-tdTHz, we evaluated the severity of myelin deficit lesions in rhesus monkey brain induced by experimental autoimmune encephalomyelitis, which is the most-studied animal model of multiple sclerosis. The results well matched the pathological analysis, indicating that PCA-tdTHz is a quick, powerful, evolving tool for identification and evaluation myelin deficit in preclinical animals and potentially in para-clinical human biopsy.

Terahertz Spectroscopic Diagnosis of Myelin Deficit Brain in Mice and Rhesus Monkey with Chemometric Techniques.

During tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3 cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.

Bcl6 Preserves the Suppressive Function of Regulatory T Cells During Tumorigenesis.

Follicular regulatory T cells (Tfrs), a specialized subset of regulatory T cells (Tregs), have a particular role in the control of follicular helper T cell-driven germinal center (GC) responses. Following differentiation signals similar to those received by follicular helper T cells (Tfhs), Tfrs gain expression of characteristic chemokine receptors and transcription factors, such as CXCR5 and Bcl-6, allowing them to migrate into the B-cell follicle and perform in situ suppression. Thus, together with Tfhs, Tfrs help maintaining an optimized GC-reaction. However, the mechanism underlying the Treg-to-Tfr transition remains obscure. Here, we established a highly reproducible protocol for investigating the differentiation of Tregs into Tfrs by constructing spleen-chimeric mice combined with retrovirus transduction. We demonstrated that using this strategy, over 4 folds of Tregs could differentiate into Tfrs in Bcl-6 overexpression group compared to control counterparts (Migr1), and Bcl-6 could efficiently promote Tfr differentiation during acute viral infection. Hence, this method provides us an easy access to investigate the factors that regulate the differentiation program that converts Tregs into Tfrs, which will enhance our understanding of the networks regulating GC-reaction and shed new light on the molecular basis of immune homeostasis.

A novel strategy to investigate the factors regulating the Treg to Tfr transition during acute viral infection.

Cytotoxic CD8 T cells are the main focus of efforts to understand anti-tumor immunity and immunotherapy. The adoptive transfer of tumor-reactive cytotoxic CD8 T lymphocytes expanded and differentiated  has long been considered the primary strategy in adaptive anti-tumor immunity, however, the majority of the transferred tumor antigen-specific CD8 T cells differentiated into CD39CD69 exhausted progenies, limiting its effects in repressing tumor growth. Contrarily, less attention has been addressed to the role of CD4 T cells during tumorigenesis. Using a mouse model of metastatic melanoma, we found that transferring tumor-specific CD4 T cells into recipients induces substantial regression of the established metastatic tumors. Notably,  activated CD4 T cells developed into cytotoxic CD4 T cells  and get exhausted gradually. The blockade of PD-L1 signaling resulted in an expansion of tumor specific CD4 T cells, which could better control the established metastatic melanoma. Moreover, the tumor-specific memory CD4 T cell can prevent mice from tumor metastasis, and the tumor-specific effector CD4 T cells can also mitigate the established metastatic tumor. Overall, our findings suggest a novel mechanism of CD4 T cells in curtailing tumor metastasis and confirm their therapeutic role in combination with PD-L1 blockade in cancer immunotherapy. Hence, a better understanding of cytotoxic CD4 T cell-mediated tumor regression could provide an alternative choice for patients exhibiting suboptimal or no response to CD8 T cell-based immunotherapies.

Tumor-Specific CD4 T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4 T Cells.

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8 T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8 T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8 T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8 cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (T) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-T cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-T cells could be harnessed to potentiate anti-tumor immunotherapy.

Qiao Liu

Institute of Immunology,
Institute of Cancer,
Xinqiao Hospital,
Institute of Cancer, Xinqiao Hospital

Third Military Medical University

Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8⁺ T Cells in Mice

Draining Lymph Node Metastasis Model for Assessing the Dynamics of Antigen-Specific CD8⁺ T Cells During Tumorigenesis

Qiao Liu

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Institute of Immunology,Institute of Cancer,Xinqiao Hospital,Institute of Cancer, Xinqiao Hospital

Third Military Medical University

Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice

Draining Lymph Node Metastasis Model for Assessing the Dynamics of Antigen-Specific CD8+ T Cells During Tumorigenesis

Institute of Immunology,
Institute of Cancer,
Xinqiao Hospital,
Institute of Cancer, Xinqiao Hospital

Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8⁺ T Cells in Mice

Draining Lymph Node Metastasis Model for Assessing the Dynamics of Antigen-Specific CD8⁺ T Cells During Tumorigenesis