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 ...

Sun Yat-sen University

Elucidation of the mechanisms of T-cell-mediated antitumor responses will provide information for the rational design and development of cancer immunotherapies. Here, we found that calnexin, an endoplasmic reticulum (ER) chaperone protein, is significantly upregulated in oral squamous cell carcinoma (OSCC). Upregulation of its membranous expression on OSCC cells is associated with inhibited T-cell infiltration in tumor tissues and correlates with poor survival of patients with OSCC. We found that calnexin inhibits the proliferation of CD4 and CD8 T cells isolated from the whole blood of healthy donors and patients with OSCC and inhibits the secretion of IFNγ, TNFα, and IL2 from these cells. Furthermore, in a melanoma model, knockdown of calnexin enhanced the infiltration and effector functions of T cells in the tumor microenvironment and conferred better control of tumor growth, whereas treatment with a recombinant calnexin protein impaired the infiltration and effector functions of T cells and promoted tumor growth. We also found that calnexin enhanced the expression of PD-1 on CD4 and CD8 T cells by restraining the DNA methylation status of a CpG island in the PD-1 promoter. Thus, this work uncovers a mechanism by which T-cell antitumor responses are regulated by calnexin in tumor cells and suggests that calnexin might serve as a potential target for the improvement of antitumor immunotherapy.

Calnexin Impairs the Antitumor Immunity of CD4 and CD8 T Cells.

Programmed death 1 (PD-1) blockade has great effect in the prevention of oral precancerous lesions, but the drug resistance has also been observed. The determinants of immune resistance during the malignant transformation are poorly understood.

Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis.

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.

Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity.

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 < 0.001) and relapse-free survival (RFS) rate (88.9% vs. 63.4%, 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 < 0.001), and their combination provided a higher predictive accuracy (AUC = 0.730; 95% CI, 0.654-0.805). In conclusion, our results suggest that TLS is an independent positive prognostic factor for OSCC patients. These findings provide a theoretical basis for the future diagnostic and therapeutic value of TLSs in OSCC treatment.

Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma.

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.

High Abundance of Intratumoral γδ T Cells Favors a Better Prognosis in Head and Neck Squamous Cell Carcinoma: A Bioinformatic Analysis.

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).

TCF-1 maintains CD8 T cell stemness in tumor microenvironment.

Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis.

In the last decade, immune checkpoint blockade (ICB) has revolutionized the standard of treatment for solid tumors. Despite success in several immunogenic tumor types evidenced by improved survival, ICB remains largely unresponsive, especially in "cold tumors" with poor lymphocyte infiltration. In addition, side effects such as immune-related adverse events (irAEs) are also obstacles for the clinical translation of ICB. Recent studies have shown that focused ultrasound (FUS), a non-invasive technology proven to be effective and safe for tumor treatment in clinical settings, could boost the therapeutic effect of ICB while alleviating the potential side effects. Most importantly, the application of FUS to ultrasound-sensitive small particles, such as microbubbles (MBs) or nanoparticles (NPs), allows for precise delivery and release of genetic materials, catalysts and chemotherapeutic agents to tumor sites, thus enhancing the anti-tumor effects of ICB while minimizing toxicity. In this review, we provide an updated overview of the progress made in recent years concerning ICB therapy assisted by FUS-controlled small-molecule delivery systems. We highlight the value of different FUS-augmented small-molecules delivery systems to ICB and describe the synergetic effects and underlying mechanisms of these combination strategies. Furthermore, we discuss the limitations of the current strategies and the possible ways that FUS-mediated small-molecule delivery systems could boost novel personalized ICB treatments for solid tumors.

Focused ultrasound-mediated small-molecule delivery to potentiate immune checkpoint blockade in solid tumors.

Author Correction: Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis.

The neck management of clinical-nodal negative (cN0) oral squamous cell carcinoma (OSCC) remains controversial. Elective neck dissection (END) and observation are the main strategies, but it is still not clear who could benefit the most from END. The purpose of this study was to clarify the potential clinical factors that affect the therapeutic value of END and to explore the actual characteristics associated with benefit from END.

Article	Year
Calnexin Impairs the Antitumor Immunity of CD4 and CD8 T Cells. Cancer immunology research\| PubMed ID: 30401678	2019
Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis. Journal of experimental & clinical cancer research : CR\| PubMed ID: 31291983	2019
Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 31350312	2019
Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma. International journal of oral science\| PubMed ID: 32934197	2020
High Abundance of Intratumoral γδ T Cells Favors a Better Prognosis in Head and Neck Squamous Cell Carcinoma: A Bioinformatic Analysis. Frontiers in immunology\| PubMed ID: 33101298	2020
TCF-1 maintains CD8 T cell stemness in tumor microenvironment. Journal of leukocyte biology\| PubMed ID: 34047386	2021
Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis. Cellular & molecular immunology\| PubMed ID: 36859455	2023
Focused ultrasound-mediated small-molecule delivery to potentiate immune checkpoint blockade in solid tumors. Frontiers in pharmacology\| PubMed ID: 37180717	2023
Author Correction: Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis. Cellular & molecular immunology\| PubMed ID: 37225839	2023
Do patients with cN0 oral squamous cell carcinoma benefit from elective neck dissection? A large-scale population-based study. BMC oral health\| PubMed ID: 38184544	2024

Shuqiong Wen

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