Topic Editors

Department of Pathology, Faculty of Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan
ICM—Paris Brain Institute, Pitié Salpêtrière Hospital, 47, bd de l'Hôpital, 75013 Paris, France

The Tumor Microenvironment and Immune Checkpoint: Implications for Current and Emergent Immunotherapies

Abstract submission deadline
closed (20 September 2022)
Manuscript submission deadline
closed (20 December 2022)
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Topic Information

Dear Colleagues,

Immunotherapy uses the body’s natural defenses (immune system) to fight disease. For example, our immune system can help to destroy cancer cells. Immuno-oncology is a type of immunotherapy that is directed against cancer.

There are two main parts of the immune system:

(1) Innate immunity (also known as built-in immune protection) has mechanisms that are prepared to act immediately, such as the skin, inner lining of the gut and lungs, stomach acid, intestinal bacteria, and leukocytes (neutrophils) that can find and kill bacteria.

In innate immunity, pathogens are recognized by receptors encoded in the germline. The receptors, known as pattern recognition receptors (PPRs), have a broad specificity for pathogen-associated molecular patterns (PAMPs).

Innate immune cells are granulocytes (neutrophils, eosinophils, basophils, mast cells), monocytes, macrophages, dendritic cells, and innate lymphoid cells (cytotoxic Natural Killer (NK) cells, and several noncytotoxic cells (IL1, 2, etcetera)).

(2) Acquired immunity is immune protection that is “learned.”

After being exposed to certain diseases and a type of bacteria, fungus, or virus for the first time, the immune system develops memory and responds quicker and better the second time.

Lymphocytes are involved in the acquired immune response.

B cells/lymphocytes make antibodies that lock onto the surface of bacteria or viruses. B lymphocytes are part of the memory of the immune system.

There are different kinds of T lymphocytes: helper T cells (Th) and killer/cytotoxic T cells (Tc). Th cells stimulate B cells to make antibodies and help Tc cells to develop. Tc cells kill the body’s own cells infected by viruses or bacteria.

In adaptive immunity, pathogens are recognized by receptors that are generated randomly. These receptors recognize epitopes (polypeptides). The receptors are B-cell (BCR) and T-cell (TCR) receptors. The response is slow (3–5 days) and has memory.

The tumor microenvironment (TME) is comprised of the tumor, the extracellular matrix (ECM), and variable infiltration by nontransformed cells, including vascular vessels, fibroblasts, and immune system infiltrates. The TME plays a major role in tumor initiation, progression, infiltration and metastasis, and resistance to treatment. The tumoral immune microenvironment comprises variable percentages of CD8+Tc, naïve CD4+T cells, FOXP3+ regulatory T lymphocytes (Tregs), B cells, neutrophils, macrophages, NK cells, and dendritic cells. Macrophages, known as tumor-associated macrophages (TAMs), are a key component of the microenvironment. These M2-like TAMs are associated with tumor migration and invasion, metastasis, growth, angiogenesis, tissue remodeling, and inhibiting the host immune response (Treg induction, inactivation of T cells, etcetera). Relevant markers associated with TAMs are PD-L1/L2, MMPs, M-CSF, CSF1R, IL-10, TGFB, prostaglandins, IDO1/2, etcetera.

The immune checkpoint refers to the mechanisms that the immune system uses to avoid collateral damage during the physiological immune response and maintain self-tolerance. Ligand–receptor interactions are mediated by co-stimulatory molecules such as CD80, CD86, GITRL, and ICOSLG expressed by antigen-presenting cells (APCs), and CD28, GITR, and ICOS expressed by T cells. Conversely, coinhibitory signaling suppresses T cell activation using PD-1, CTLA-4, and LAG3 expressed by T cells.

In the tumor microenvironment, cancer cells take advantage of the coinhibitory pathway, expressing markers such as PD-L1 (Figure 1). In addition, tumor-associated macrophages (TAMs) can also express PD-L1 and CSF1R (Figure 2).

Jisc logo

Figure 1. PD-L1 expression in diffuse large B-cell lymphoma (DLBCL) and the correlation with the poor prognosis of patients.

AI 2021, 2(1), 106-134; https://doi.org/10.3390/ai2010008

Jisc logo

Figure 2. CSF1R expression by tumor-associated macrophages (TAMs) in DLBCL and the correlation with other markers using a neural network.

Hemato 2021, 2(2), 182-206; https://doi.org/10.3390/hemato2020011

Other factors are immunostimulatory signals for turning up cold tumors, which are not restricted to neoantigens derived from mutations. For instance, these include stress signals (DAMPs), the DNA damage response, and metabolic changes in the TME. Finally, the key role of immunosenescence and/or epitranscriptomic changes in immune cells that challenge tumor immunity must also be considered.

Some kinds of cancer are susceptible to treatment with immunotherapy because cancer cells are different from normal cells, so the immune system recognizes them and kills these abnormal cells. There are different types of immunotherapies:

  • Monoclonal antibodies (MABs), which recognize and attach certain proteins on cell surfaces.
  • Checkpoint inhibitors (immune checkpoint blockade (ICB) therapies).
  • Cytokines, which help boost the immune system.
  • Vaccines, which help recognize and attack cancer.
  • CAR T-cell therapy (also known as adoptive cell transfer).

Since standard chemotherapeutic agents and radiation, as well as targeted therapies, elicit/instigate an antitumor immune response, the combination of therapeutic modalities is the best treatment approach. Nevertheless, the current ICB therapies have a limitation in that they acquire resistance mechanisms.

This Topic accepts manuscripts that deal with all aspects of the immune response in hematological neoplasia and cancer, from basic to clinical research and integrative analyses.

Dr. Joaquim Carreras
Dr. Luis J. Castro-Vega
Topic Editors

Keywords

  • hematological neoplasia
  • cancer
  • immune microenvironment
  • immune checkpoint
  • immuno-oncology
  • tumor-associated macrophages

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Cancers
cancers
5.2 8.0 2009 17.9 Days CHF 2900
Cells
cells
6.0 9.9 2012 16.6 Days CHF 2700
Healthcare
healthcare
2.8 3.5 2013 19.5 Days CHF 2700
Hemato
hemato
- 1.3 2020 28.1 Days CHF 1000
Journal of Clinical Medicine
jcm
3.9 5.7 2012 17.9 Days CHF 2600
Vaccines
vaccines
7.8 8.9 2013 19.2 Days CHF 2700

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Published Papers (9 papers)

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11 pages, 860 KiB  
Article
Awareness and Perceptions of the Impact of Tonsillectomy on the Level of Immunity and Autoimmune Diseases among the Adult Population in Abha City, Kingdom of Saudi Arabia
by Ayoub A. Al-shaikh, Abdullah Alhelali, Syed Esam Mahmood, Fatima Riaz, Abdulrahim Ali Hassan Hassan, Abduaelah Ali H Hassan, Bandar Mohammed Mushabbab Asiri, Abdulaziz Saad Mohammed Al-shahrani, Abdullah Jallwi Mohammed Korkoman, Abdullah Fahad Alahmari, Abeer Ali Hassan Hassan, Mohammed O. Shami, Ausaf Ahmad, Rishi K. Bharti and Md. Zeyaullah
Healthcare 2023, 11(6), 890; https://doi.org/10.3390/healthcare11060890 - 20 Mar 2023
Viewed by 1842
Abstract
The widespread misconception that tonsillectomy leads to a decrease in immunity may lead to fear and avoidance of the operation. This can result in a deterioration of the situation, such as sleep-related breathing issues, frequent infections, and an increase in complications. The current [...] Read more.
The widespread misconception that tonsillectomy leads to a decrease in immunity may lead to fear and avoidance of the operation. This can result in a deterioration of the situation, such as sleep-related breathing issues, frequent infections, and an increase in complications. The current research was conducted to assess the awareness and perception with respect to the impact of tonsillectomy on the immune system and to assess the awareness and perception of the relationship between autoimmune diseases and tonsillectomy. This 6-month descriptive cross-sectional online questionnaire survey was conducted among individuals who were 18 years and above living in Abha city, Saudi Arabia. Out of the 800 study subjects, 104 (13%) had undergone tonsillectomy. Statistically significant associations were found between age group, education, income, and occupation among those who had undergone tonsillectomy. Multivariate logistic regression analysis showed that ages 18–30 years and 31–40 years (OR: 2.36, 95% CI: 1.18–4.71, and OR: 1.46, 95% CI: 0.53–3.97) and education levels of high school, bachelors, and above (OR: 8.30, 95% CI: 3.05–22.58 and OR: 10.89, 95% CI: 4.23–28.05) were found to be associated with tonsillectomy status of the subjects. On the contrary, income levels of 5000–9000 and >9000 (OR: 0.65, 95% CI: 0.36–1.17 and OR: 0.78, 95%CI: 0.42–1.42) and male gender (OR: 0.79, 95% CI: 0.52–1.19) were found to be associated with non-tonsillectomy status of subjects. Almost 36% of study subjects thought that tonsillectomy affects immunity. Only 18% of study subjects thought that there is a relationship between tonsillectomy and autoimmune diseases. About one-third of the respondents had received this information from community members and social media. A small number of study subjects relied on public awareness programs. Therefore, social media can play a vital role in the community to remove misconceptions regarding tonsillectomy and its effect on immunity and autoimmune disease. Further educational interventional studies are required to see the correction to the public perception of tonsillectomy and its effect on immunity and autoimmune diseases. Full article
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9 pages, 1031 KiB  
Communication
Expression of pH-Sensitive GPCRs in Peritoneal Carcinomatosis of Colorectal Cancer—First Results
by Philipp von Breitenbuch, Bernadett Kurz, Susanne Wallner, Florian Zeman, Christoph Brochhausen, Hans-Jürgen Schlitt and Stephan Schreml
J. Clin. Med. 2023, 12(5), 1803; https://doi.org/10.3390/jcm12051803 - 23 Feb 2023
Cited by 3 | Viewed by 1793
Abstract
Solid tumors have an altered metabolism with a so-called inside-out pH gradient (decreased pHe < increased pHi). This also signals back to tumor cells via proton-sensitive ion channels or G protein-coupled receptors (pH-GPCRs) to alter migration and proliferation. Nothing, however, [...] Read more.
Solid tumors have an altered metabolism with a so-called inside-out pH gradient (decreased pHe < increased pHi). This also signals back to tumor cells via proton-sensitive ion channels or G protein-coupled receptors (pH-GPCRs) to alter migration and proliferation. Nothing, however, is known about the expression of pH-GPCRs in the rare form of peritoneal carcinomatosis. Paraffin-embedded tissue samples of a series of 10 patients with peritoneal carcinomatosis of colorectal (including appendix) origin were used for immunohistochemistry to study the expression of GPR4, GPR65, GPR68, GPR132, and GPR151. GPR4 was just expressed weakly in 30% of samples and expression was significantly reduced as compared to GPR56, GPR132, and GPR151. Furthermore, GPR68 was only expressed in 60% of tumors and showed significantly reduced expression as compared to GPR65 and GPR151. This is the first study on pH-GPCRs in peritoneal carcinomatosis, which shows lower expression of GPR4 and GPR68 as compared to other pH-GPCRs in this type of cancer. It may give rise to future therapies targeting either the TME or these GPCRs directly. Full article
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17 pages, 3653 KiB  
Article
The PD-L1 Expression and Tumor-Infiltrating Immune Cells Predict an Unfavorable Prognosis in Pancreatic Ductal Adenocarcinoma and Adenosquamous Carcinoma
by Zhiwei Zhang, Qunli Xiong, Yongfeng Xu, Xuebin Cai, Lisha Zhang and Qing Zhu
J. Clin. Med. 2023, 12(4), 1398; https://doi.org/10.3390/jcm12041398 - 9 Feb 2023
Cited by 2 | Viewed by 2293
Abstract
The tumor microenvironment (TME) plays a vital role in the development, progression, and metastasis of pancreatic cancer (PC). The composition of the TME and its potential prognostic value remains to be fully understood, especially in adenosquamous carcinoma of pancreas (ASCP) patients. Immunohistochemistry was [...] Read more.
The tumor microenvironment (TME) plays a vital role in the development, progression, and metastasis of pancreatic cancer (PC). The composition of the TME and its potential prognostic value remains to be fully understood, especially in adenosquamous carcinoma of pancreas (ASCP) patients. Immunohistochemistry was used to explore the clinical significance of CD3, CD4, CD8, FoxP3, and PD-L1 expression within the TME and to identify correlations with the prognosis of PC in a series of 29 patients with ASCP and 54 patients with pancreatic ductal adenocarcinoma (PDAC). Data from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) were accessed to obtain the scRNA-seq data and transcriptome profiles. Seurat was used to process the scRNA-seq data, and CellChat was used to analyze cell–cell communication. CIBERSORT was used to approximate the constitution of tumor-infiltrating immune cell (TICs) profiles. Higher levels of PD-L1 were linked with a shorter overall survival in ASCP (p = 0.0007) and PDAC (p = 0.0594). A higher expression of CD3+ and CD8+ T-cell infiltration was significantly correlated with a better prognosis in PC. By influencing the composition of tumor-infiltrating immune cells (TICs), high levels of PD-L1 expression are linked with a shorter overall survival in ASCP and PDAC. Full article
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12 pages, 3977 KiB  
Article
Association between Early Immune-Related Adverse Events and Survival in Patients Treated with PD-1/PD-L1 Inhibitors
by You-Cheng Zhang, Tian-Chen Zhu, Run-Cong Nie, Liang-He Lu, Zhi-Cheng Xiang, Dan Xie, Rong-Zhen Luo and Mu-Yan Cai
J. Clin. Med. 2023, 12(3), 736; https://doi.org/10.3390/jcm12030736 - 17 Jan 2023
Cited by 4 | Viewed by 1611
Abstract
Background: Immune-related adverse events (irAEs) are side effects that reflect the activation of patients’ immune systems after treatment with immune checkpoint inhibitors (ICIs). However, there is no meta-analysis on the effect of early irAEs on patient survival. Thus, we assessed the association between [...] Read more.
Background: Immune-related adverse events (irAEs) are side effects that reflect the activation of patients’ immune systems after treatment with immune checkpoint inhibitors (ICIs). However, there is no meta-analysis on the effect of early irAEs on patient survival. Thus, we assessed the association between early irAEs and the survival of patients treated with ICIs. Methods: PubMed, Embase, and Web of Science were searched from May 2010 to May 2020 for all the retrospective and prospective comparative studies to evaluate the hazard ratios (HRs) for death. A random-effects model was used to calculate the pooled HR for death, and heterogeneity was assessed using I² statistics. The main outcomes were overall survival (OS) and progression-free survival (PFS). Results: A total of 11 reports with 2077 patients were included. A significant association was observed between early irAEs and a favorable clinical outcome. Patients with early irAEs had prolonged OS (HR: 0.62, 95% confidence interval (CI): 0.53–0.74, p < 0.001) and PFS (HR: 0.53, 95% CI: 0.41–0.66, p < 0.001) compared to those without; these results were confirmed using a sensitivity analysis. The irAE types, malignancy types, and sample size were correlated with patients’ clinical outcomes. Conclusions: Early irAEs, especially cutaneous irAEs, correlated with a better clinical outcome in patients treated with ICIs. Full article
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14 pages, 1801 KiB  
Article
An Inhibitory Role for Human CD96 Endodomain in T Cell Anti-Tumor Responses
by Chelsia Qiuxia Wang, Fong Chan Choy, Arleen Sanny, Takashi Murakami, Andy Hee-Meng Tan and Kong-Peng Lam
Cells 2023, 12(2), 309; https://doi.org/10.3390/cells12020309 - 13 Jan 2023
Cited by 1 | Viewed by 2887
Abstract
Immune checkpoint blockade (ICB) therapy involves the inhibition of immune checkpoint regulators which reverses their limitation of T cell anti-tumor responses and results in long-lasting tumor regression. However, poor clinical response or tumor relapse was observed in some patients receiving such therapy administered [...] Read more.
Immune checkpoint blockade (ICB) therapy involves the inhibition of immune checkpoint regulators which reverses their limitation of T cell anti-tumor responses and results in long-lasting tumor regression. However, poor clinical response or tumor relapse was observed in some patients receiving such therapy administered via antibodies blocking the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway alone or in combination, suggesting the involvement of additional immune checkpoints. CD96, a possible immune checkpoint, was previously shown to suppress natural killer (NK) cell anti-tumor activity but its role in human T cells remains controversial. Here, we demonstrate that CRISPR/Cas9-based deletion of CD96 in human T cells enhanced their killing of leukemia cells in vitro. T cells engineered with a chimeric antigen receptor (CAR) comprising human epidermal growth factor receptor 2 (EGFR2/HER2)-binding extracellular region and intracellular regions of CD96 and CD3ζ (4D5-96z CAR-T cells) were less effective in suppressing the growth of HER2-expressing tumor cells in vitro and in vivo compared with counterparts bearing CAR that lacked CD96 endodomain (4D5-z CAR-T cells). Together, our findings implicate a role for CD96 endodomain in attenuating T cell cytotoxicity and support combination tumor immunotherapy targeting multiple rather than single immune checkpoints. Full article
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20 pages, 1832 KiB  
Review
Response to Immune Checkpoint Inhibitors Is Affected by Deregulations in the Antigen Presentation Machinery: A Systematic Review and Meta-Analysis
by Maria Rasmussen, Jon Ambæk Durhuus, Mef Nilbert, Ove Andersen and Christina Therkildsen
J. Clin. Med. 2023, 12(1), 329; https://doi.org/10.3390/jcm12010329 - 31 Dec 2022
Cited by 6 | Viewed by 2580
Abstract
Immune checkpoint inhibitors (ICI) targeting programmed death 1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) have shown promising results against multiple cancers, where they reactivate exhausted T cells primed to eliminate tumor cells. ICI therapies have been particularly successful in [...] Read more.
Immune checkpoint inhibitors (ICI) targeting programmed death 1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) have shown promising results against multiple cancers, where they reactivate exhausted T cells primed to eliminate tumor cells. ICI therapies have been particularly successful in hypermutated cancers infiltrated with lymphocytes. However, resistance may appear in tumors evading the immune system through alternative mechanisms than the PD-1/PD-L1 or CTLA-4 pathways. A systematic pan-cancer literature search was conducted to examine the association between alternative immune evasion mechanisms via the antigen presentation machinery (APM) and resistance towards ICI treatments targeting PD-1 (pembrolizumab and nivolumab), PD-L1 (durvalumab, avelumab, and atezolizumab), and CTLA-4 (ipilimumab). The APM proteins included the human leucocyte antigen (HLA) class I, its subunit beta-2 microglobulin (B2M), the transporter associated with antigen processing (TAP) 1, TAP2, and the NOD-like receptor family CARD domain containing 5 (NLRC5). In total, 18 cohort studies (including 21 original study cohorts) containing 966 eligible patients and 9 case studies including 12 patients were reviewed. Defects in the APM significantly predicted poor clinical benefit with an odds ratio (OR) of 0.39 (95% CI 0.24–0.63, p < 0.001). The effect was non-significant, when considering complete and partial responses only (OR = 0.52, 95% CI 0.18–1.47, p = 0.216). In summary, the APM contains important targets for tumorigenic alterations which may explain insensitivity towards ICI therapy. Full article
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14 pages, 22369 KiB  
Article
Tumor Cell-Intrinsic BTLA Receptor Inhibits the Proliferation of Tumor Cells via ERK1/2
by Tian-You Cheng, Ya-Juan Liu, Hong Yan, Yi-Bo Xi, Li-Qiang Duan, Yang Wang, Tian-Tian Zhang, Yin-Min Gu, Xiao-Dong Wang, Chang-Xin Wu and Shan Gao
Cells 2022, 11(24), 4021; https://doi.org/10.3390/cells11244021 - 12 Dec 2022
Cited by 9 | Viewed by 2079
Abstract
B and T lymphocyte attenuator (BTLA) is an immune checkpoint molecule that mediates the escape of tumor cells from immunosurveillance. Consequently, BTLA and its ligand herpesvirus entry mediator (HVEM) are potentially immunotherapeutic targets. However, the potential effects of BTLA on tumor cells remain [...] Read more.
B and T lymphocyte attenuator (BTLA) is an immune checkpoint molecule that mediates the escape of tumor cells from immunosurveillance. Consequently, BTLA and its ligand herpesvirus entry mediator (HVEM) are potentially immunotherapeutic targets. However, the potential effects of BTLA on tumor cells remain incompletely unknown. Here, we show that BTLA is expressed across a broad range of tumor cells. The depletion of BTLA or HVEM promotes cell proliferation and colony formation, which is reversed by the overexpression of BTLA in BTLA knockout cells. In contrast, overexpression of BTLA or HVEM inhibits tumor cell proliferation and colony formation. Furthermore, the proliferation of a subpopulation with high BTLA was also significantly slower than that of the low BTLA subpopulation. Mechanistically, the coordination of BTLA and HVEM inhibits its major downstream extracellular regulated protein kinase (ERK1/2) signaling pathway, thus preventing tumor cell growth. This study demonstrates that tumor cell-intrinsic BTLA/HVEM is a potential tumor suppressor and is likely to have a potential antagonist for immunotherapy, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment. Full article
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19 pages, 4997 KiB  
Article
Copy Number Alteration and Mutational Profile of High-Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements, Diffuse Large B-Cell Lymphoma with MYC-Rearrangement, and Diffuse Large B-Cell Lymphoma with MYC-Cluster Amplification
by Masashi Miyaoka, Yara Yukie Kikuti, Joaquim Carreras, Atsushi Ito, Haruka Ikoma, Sakura Tomita, Hiroshi Kawada, Giovanna Roncador, Silvia Bea, Elias Campo and Naoya Nakamura
Cancers 2022, 14(23), 5849; https://doi.org/10.3390/cancers14235849 - 27 Nov 2022
Cited by 4 | Viewed by 2268
Abstract
Diffuse large B-cell lymphoma (DLBCL) with MYC alteration is classified as high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double/triple-hit lymphoma; DHL/THL), DLBCL with MYC rearrangement (single-hit lymphoma; SHL) and DLBCL with MYC-cluster amplification (MCAD). To elucidate the genetic features [...] Read more.
Diffuse large B-cell lymphoma (DLBCL) with MYC alteration is classified as high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double/triple-hit lymphoma; DHL/THL), DLBCL with MYC rearrangement (single-hit lymphoma; SHL) and DLBCL with MYC-cluster amplification (MCAD). To elucidate the genetic features of DHL/THL, SHL, and MCAD, 23 lymphoma cases from Tokai University Hospital were analyzed. The series included 10 cases of DHL/THL, 10 cases of SHL and 3 cases of MCAD. The analysis used whole-genome copy number microarray analysis (OncoScan) and a custom-made next-generation sequencing (NGS) panel of 115 genes associated with aggressive B-cell lymphomas. The copy number alteration (CNA) profiles were similar between DHL/THL and SHL. MCAD had fewer CNAs than those of DHL/THL and SHL, except for +8q24. The NGS profile characterized DHL/THL with a higher “mutation burden” than SHL (17 vs. 10, p = 0.010), and the most relevant genes for DHL/THL were BCL2 and SOCS1, and for SHL was DTX1. MCAD was characterized by mutations of DDX3X, TCF3, HLA-A, and TP53, whereas MYC was unmutated. In conclusion, DHL/THL, SHL, and MCAD have different profiles. Full article
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15 pages, 1073 KiB  
Review
Cancer Cell Metabolism Reprogramming and Its Potential Implications on Therapy in Squamous Cell Carcinoma of the Head and Neck: A Review
by Francesco Perri, Giuseppina Della Vittoria Scarpati, Monica Pontone, Maria Luisa Marciano, Alessandro Ottaiano, Marco Cascella, Francesco Sabbatino, Agostino Guida, Mariachiara Santorsola, Piera Maiolino, Ernesta Cavalcanti, Giulia Togo, Franco Ionna and Francesco Caponigro
Cancers 2022, 14(15), 3560; https://doi.org/10.3390/cancers14153560 - 22 Jul 2022
Cited by 6 | Viewed by 2129
Abstract
Carcinogenesis is a multistep process that consists of the transformation of healthy cells into cancer cells. Such an alteration goes through various stages and is closely linked to random mutations of genes that have a key role in the neoplastic phenotype. During carcinogenesis, [...] Read more.
Carcinogenesis is a multistep process that consists of the transformation of healthy cells into cancer cells. Such an alteration goes through various stages and is closely linked to random mutations of genes that have a key role in the neoplastic phenotype. During carcinogenesis, cancer cells acquire and exhibit several characteristics including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, and expressing an immune phenotype, which allow them to evade recognition and destruction through cognate immune cells. In addition, cancer cells may acquire the ability to reprogram their metabolism in order to further promote growth, survival, and energy production. This phenomenon, termed metabolic reprogramming, is typical of all solid tumors, including squamous carcinomas of the head and neck (SCCHN). In this review, we analyze the genetic and biological mechanisms underlying metabolic reprogramming of SCCHN, focusing on potential therapeutic strategies that are able to counteract it. Full article
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