In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways

Abdeladhim, Maha; Karnell, Jodi L.; Rieder, Sadiye Amcaoglu

doi:10.3389/fimmu.2022.1033705

Cited by 9 publications

(9 citation statements)

References 347 publications

(383 reference statements)

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“…An immune receptor/immune checkpoint present on T cells, regulatory T cells (CD4 + CD25 + Foxp3 + T regs ) and CD56 dim NK cells is a T cell immunoreceptor with Ig and ITIM domains (TIGIT protein), also known as WUCAM/Vstm3. It inhibits effector T cell activation in vivo and NK cytotoxicity by binding to CD115 and CD112 molecules on dendritic cells (DCs) and macrophages (TAMs/MФ), but also to ligands on the tumour cell surface, thus facilitating the mechanisms of immune escape in the cancer immune cycle [ 405 , 406 , 407 , 408 ]. Importantly, TIGIT and programmed death-ligand 1 (PD-1) have been shown to be upregulated on tumour antigen-specific CD8 + T cells and CD8 + tumour infiltrating lymphocytes (TILs) in both HNSCC patients and mouse models; in addition, their level was correlated with other immune-checkpoint molecules, i.e., PD-1, TIM-3 and LAG-3 [ 409 , 410 , 411 ].…”

Section: Resultsmentioning

confidence: 99%

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Starska

2023

Cancers

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Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the most common cancer worldwide in 2020, according to the latest GLOBOCAN data, representing the seventh most prevalent human malignancy. Despite great advances in surgical techniques and the application of modern combinations and cytotoxic therapies, HNSCC remains a leading cause of death worldwide with a low overall survival rate not exceeding 40–60% of the patient population. The most common causes of death in patients are its frequent nodal metastases and local neoplastic recurrences, as well as the relatively low response to treatment and severe drug resistance. Much evidence suggests that the tumour microenvironment (TME), tumour infiltrating lymphocytes (TILs) and circulating various subpopulations of immunocompetent cells, such regulatory T cells (CD4+CD25+Foxp3+Tregs), cytotoxic CD3+CD8+ T cells (CTLs) and CD3+CD4+ T helper type 1/2/9/17 (Th1/Th2/Th9/Th17) lymphocytes, T follicular helper cells (Tfh) and CD56dim/CD16bright activated natural killer cells (NK), carcinoma-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (N1/N2 TANs), as well as tumour-associated macrophages (M1/M2 phenotype TAMs) can affect initiation, progression and spread of HNSCC and determine the response to immunotherapy. Rapid advances in the field of immuno-oncology and the constantly growing knowledge of the immunosuppressive mechanisms and effects of tumour cancer have allowed for the use of effective and personalized immunotherapy as a first-line therapeutic procedure or an essential component of a combination therapy for primary, relapsed and metastatic HNSCC. This review presents the latest reports and molecular studies regarding the anti-tumour role of selected subpopulations of immunocompetent cells in the pathogenesis of HNSCC, including HPV+ve (HPV+) and HPV−ve (HPV−) tumours. The article focuses on the crucial regulatory mechanisms of pro- and anti-tumour activity, key genetic or epigenetic changes that favour tumour immune escape, and the strategies that the tumour employs to avoid recognition by immunocompetent cells, as well as resistance mechanisms to T and NK cell-based immunotherapy in HNSCC. The present review also provides an overview of the pre- and clinical early trials (I/II phase) and phase-III clinical trials published in this arena, which highlight the unprecedented effectiveness and limitations of immunotherapy in HNSCC, and the emerging issues facing the field of HNSCC immuno-oncology.

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Section: Resultsmentioning

confidence: 99%

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Starska

2023

Cancers

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“…Growing evidence demonstrates that Treg promotes tumor immune escape through different mechanisms. PD‐1, PD‐L1, and CTLA‐4 are also over expressed on PD‐1/PD‐L1‐producing Tregs in the TME, which transmit inhibitory signals 149,152 . It is noteworthy that PD‐1/PD‐L1 pathway is one of the important mechanisms by which Treg inhibits T cell activity and thus exerts its immunosuppressive function 149,152,153 .…”

Section: Circulating Immune Cells In Antitumor Immunotherapymentioning

confidence: 99%

“…As Tregs are known to be crucial in immune homeostasis and autoimmunity prevention, a decrease in Treg function may trigger overreactive autoimmune responses and disorders. 149 , 150 Tregs have been shown to increase in periphery and TIL of patients with NSCLC, breast cancer, colorectal cancer, and other malignancies. 4 , 151 Growing evidence demonstrates that Treg promotes tumor immune escape through different mechanisms.…”

Section: Circulating Immune Cells In Antitumor Immunotherapymentioning

confidence: 99%

Progresses in biomarkers for cancer immunotherapy

Lin,

Zong,

Zhang

et al. 2023

MedComm

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Currently, checkpoint inhibitor‐based immunotherapy has emerged as prevailing treatment modality for diverse cancers. However, immunotherapy as a first‐line therapy has not consistently yielded durable responses. Moreover, the risk of immune‐related adverse events increases with combination regimens. Thus, the development of predictive biomarkers is needed to optimize individuals benefit, minimize risk of toxicities, and guide combination approaches. The greatest focus has been on tumor programmed cell death‐ligand 1 (PD‐L1), microsatellite instability (MSI), and tumor mutational burden (TMB). However, there remains a subject of debate due to thresholds variability and significant heterogeneity. Major unmet challenges in immunotherapy are the discovery and validation of predictive biomarkers. Here, we show the status of tumor PD‐L1, MSI, TMB, and emerging data on novel biomarker strategies with oncogenic signaling and epigenetic regulation. Considering the exploration of peripheral and intestinal immunity has served as noninvasive alternative in predicting immunotherapy, this review also summarizes current data in systemic immunity, encompassing solute PD‐L1 and TMB, circulating tumor DNA and infiltrating lymphocytes, routine emerging inflammatory markers and cytokines, as well as gut microbiota. This review provides up‐to‐date information on the evolving field of currently available biomarkers in predicting immunotherapy. Future exploration of novel biomarkers is warranted.

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“…The interplay of PD-1 and PD-L1 contributes to the development of inducible Tregs. In vitro and in vivo, PD-L1-negative APCs have a diminished capacity to produce Tregs [ 183 ]. Immune checkpoints are critical for the tolerance and, in particular, maintenance of Tregs.…”

Section: Implication Of Autophagy In the Commonalities Between Autoim...mentioning

confidence: 99%

Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy

Műzes

Sípos

2023

Biomedicines

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The immune system and autophagy share a functional relationship. Both innate and adaptive immune responses involve autophagy and, depending on the disease’s origin and pathophysiology, it may have a detrimental or positive role on autoimmune disorders. As a “double-edged sword” in tumors, autophagy can either facilitate or impede tumor growth. The autophagy regulatory network that influences tumor progression and treatment resistance is dependent on cell and tissue types and tumor stages. The connection between autoimmunity and carcinogenesis has not been sufficiently explored in past studies. As a crucial mechanism between the two phenomena, autophagy may play a substantial role, though the specifics remain unclear. Several autophagy modifiers have demonstrated beneficial effects in models of autoimmune disease, emphasizing their therapeutic potential as treatments for autoimmune disorders. The function of autophagy in the tumor microenvironment and immune cells is the subject of intensive study. The objective of this review is to investigate the role of autophagy in the simultaneous genesis of autoimmunity and malignancy, shedding light on both sides of the issue. We believe our work will assist in the organization of current understanding in the field and promote additional research on this urgent and crucial topic.

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In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways

Cited by 9 publications

References 347 publications

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Progresses in biomarkers for cancer immunotherapy

Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy

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