Tumor Microenvironment in Head and Neck Squamous Cell Carcinoma: A Focus on Tumor-Infiltrating Lymphocytes
For more progress in head and neck squamous cell carcinoma (HNSCC) immuno-oncology, further understanding of interactions between tumor and immune system as well as factors in the tumor microenvironment is required. HNSCC is seriously infiltrated by lymphocytes but is known to be highly immunosuppressive. The aim of this review is to highlight the complexity of tumor microenvironment and tumor- immune cells interaction in the HNSCC, in order to improve understanding of tumorigenesis and disease progression in HNSCC patient and to provide valuable information about prognostic markers. The main goal of this review is to discuss the role of the tumor infiltrating lymphocytes in tumor progression, their cross-talk with other components of the tumor microenvironment as well as their roles in carcinogenesis, metastasis process, treatment, and prognosis in head and neck squamous cell carcinomas.
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of upper aerodigestive tract malignancies that accounts for 90% of all head and neck cancer cases. HNSCC is the sixth most common cancer by incidence, and a leading cause of cancer-related death . Besides alcohol and smoking, human papillomavirus (HPV) has been recently regarded as a major etiological factor for a subgroup of HNSCC including oropharynx .
Despite the improvement of treatment regimens, the 5-year survival of HNSCC patients is only about 40-50% . Tumor micrometastases to lymphovascular and/or perineural are associated with increased recurrence rate . Accordingly, the development of new treatment modalities and establishing accurate prognostic markers is always demand.
Recently it has been shown that tumor aggressiveness and therapy resistance are extremely influenced by the interactions between tumor cells and their surrounding microenvironment .
HNSCC tumors are highly infiltrated by different types of immune cells which are considered as important elements of TME for predicting clinical outcome of the disease . Although the presence of certain immune cells in the tumor microenvironment (TME) is related to favorable outcome , some indications propose that antitumor immune responses are impaired in HNSCC and are related to disease progression .
Different aspects of the HNSCC tumor microenvironment including the influence of tumor cells-immune cells interactions on the activation and regulation of cell-mediated immune responses have remained to be cleared. Comprehensive understanding of the interactions between immune cells and tumor microenvironment components in HNSCC may lead to the development of new cancer therapy modalities to improve immune responses against this highly mortal malignancy.
The purpose of this article is to review the main components of the tumor microenvironment in HNSCC, their cross talk and the effect of metabolic changes on the structure/ function of the tumor microenvironment.
An overview of the tumor microenvironment in HNSCC
The tumor microenvironment is a complex and dynamic network of cellular and non-cellular components including malignant cells, cancer-associated fibroblasts, endothelial cells, infiltrating immune cells, and secretory mediators such as exosomes which contribute to the establishment of complex crosstalk with the tumor entity . It has been shown that some tumor microenvironment-associated factors such as hypoxia , inflammation and angiogenesis  may influence the infiltration of lymphocytes to HNSCC and play pivotal roles in the tumor development, invasion and metastasis. Environmental factors such as tobacco or alcohol have been shown to influence the progression of HNSCC through the induction of genetic alterations, which in turn result in the suppression of immune system, the transformation of stromal cells and induction of chronic inflammation .
As a highly immunomodulatory tumor, HNSCC takes advantage of genetic and environmental mechanisms such as the selection of poorly immunogenic cancer cell subsets, production of proinflammatory and immunosuppressive cytokines, secretion of exosomes, induction of immunosuppressive immune cells and expression of immune checkpoint pathway molecules . The mechanism by which tumor infiltrating cells become suppressed in the tumor microenvironment is not completely understood, though it has been associated with the presence of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells (MDSCs). Recent studies have also shown that the release of tumor-derived exosomes is related to the immunosuppression in the tumor microenvironment .
Exosomes are small membranous vesicles originated from endocytic compartments which are released to the extracellular spaces. Exosomes have recently been identified in several human malignancies including melanoma , Glioblastoma , colorectal cancer  and Hepatocellular cancer. Tumor-derived exosomes are composed of different proteins and microRNAs and play a key role in the cross-communication between tumors and the cells of the immune system, promoting the immune evasion of tumors [23, 32-35]. The presence of Exosomes, in HNSCC and some other tumors, has been correlated with advanced tumor stages. Exosomes have been considered as main contributors responsible for progression, metastasis, survival, immune regulation and other invasive characteristics of tumors which function through communication with cells in the tumor microenvironment. Although the underlying mechanisms of the production of exosomes are yet to be explored, it has been shown that exosomes act as carriers for immunosuppressive molecules delivering them to the target immune cells. Recent studies have shown that increased levels of immunomodulating PD-L1+exosomes isolated from blood samples of HNSCC patients are linked to tumor progression and immune suppression[36, 37].
It has been shown that exosomes have different morphology and molecular features in oral cancer patients compared to healthy individuals, which can be used as an early diagnostic marker for identifying malignant changes in high-risk cases . In the tumor microenvironment, exosomes through interaction with hypoxia, inflammation, and angiogenesis associated elements can influence the incidence and progression of tumors. In hypoxic microenvironment tumor cells stimulate generate miR-21-rich exosomes that are delivered to normoxic cells and promoted prometastatic behaviors. Moreover, exosomes derived from hypoxic oral squamous cell carcinoma (OSCC) cells increase the migration and invasion of tumor cells in a HIF-1α and HIF-2α-dependent manner .
The effect of Hypoxia, inflammation in head and neck squamous cell carcinoma microenvironment on tumor infiltrating lymphocytes
In many types of tumors including HNSCC, the inflamed microenvironment in combination with low oxygen concentration is ideal factors which contribute to tumorigenesis and angiogenesis through immune cell dysregulation such as apoptosis of cytotoxic T cells and activation of suppressor T cells [40-42]. Hypoxia inducible factor (HIF) is a transcription factor which is induced following hypoxia in the tumor microenvironment. HIF acts as a regulator of immune cells effector function through an effect on their cytokine production ability, their survival, and apoptosis . It was shown that high PD-L1 expression by the tumor cells under hypoxic conditions, which induces tumor resistance into CD8+ T cells toxic agents . In addition, HIFs display strong signaling which results in the switch of inflammatory responses to a pro-tumorigenic state by recruiting immune cells and changing their effector functions to suppress antitumor immune responses. Higher expression of HIF is reported as a negative prognosticator in patients with HNSCC . It has been reported that tumor infiltrating lymphocytes in HNSCC, which encountered low oxygen concentration, reduce production level of cytokines and granzyme due to the hindrance of Kv1.3 channels .
Inflammation, as the second factor which contributes to tumor growth, has been shown to closely relate with HNSCC development. In a murine model of HNSCC it has been observed that in premalignant stage, the level of Th1, Tc1, and Th17 increased in comparison with a control group and HNSCC-bearing mice, however, the frequency of regulatory T cells was higher in HNSCC-bearing mice . Another study showed that in established HNSCC, lower levels of proinflammatory agents were detected including CCL5, MCP-1, G-CSF, and PGE2 as compared with lesions of premalignant state . These two above mentioned studies suggest the premalignant microenvironment to be more immune stimulatory than the microenvironment of an established HNSCC. However, it remains uncertain if inflammation at the primary tumor site represents a beneficial manifestation of a patient's immune response to cancer in the tumor microenvironment or actually is a carcinogenic response that enhances tumor progression through the elaboration of regulatory cytokines such as IL-6, IL-10, and IL-17 [49-51]. Further investigations were needed in order to understand the multilateral effects of the inflammation at the primary state of the tumor.
TILs in HNSCC
Tumor-infiltrating lymphocytes (TILs) are important predictors of tumor biology and outcome. Several studies showed the presence of TILs in different tumors and functional subsets are a favorable prognostic factor for treatment and linked with patients’ clinical outcomes [52, 53].
In HNSCCs, better response to definitive chemo radiotherapy has been reported in cases with a higher number of TILs [54, 55], and better outcomes were reported following surgery with adjuvant therapy .
Presence of TILs in HNSCC indicates that this cancer can be considered as immunogenic cancer. However, the antitumor immune responses are affected by functional defects or apoptosis of both circulating and tumor-infiltrating T-cells [15, 57-61]. Moreover, numbers of TILs, their function, and location in the HNSCC microenvironment may significantly vary independently to the site and size of tumors. For example, oropharyngeal tumors contain higher levels of T-cell infiltration, compared to tumors at other sites of the head and neck [62, 63].
Studies have shown that different subsets of lymphocytes have altered or even opposite functions in the tumor microenvironment. Indeed, it has been founded that high CD8+ T cell infiltration associated with a better prognostic value and outcome in HNSCC . however, the role of a wide range of CD4+ cell subsets with different functions in the tumor microenvironment and their prognostic role remains to be elucidated[65, 66].
T cells are one of the important factors that organize the immune system to check and remove malignant cells in favor of immune surveillance [67, 68]. In several malignancies such as colorectal and ovarian cancer, high infiltration of CD8+ Cytotoxic T cells are positively correlated with prognosis and favorable outcome compared to no infiltration [69-73]. Also, it has been reported patients with HNSCC whose tumor was extremely infiltrated by CD8+ T cells have a significantly better outcome compared to patients with slight or no infiltration of CD8+ T cells [44, 55, 56, 74, 75]. However, in the study of oral cavity tumors, high level of CD8+ TILs has shown no significant prognostic value [76-78] or was positively correlated with tumor recurrence . These results could be a consequence of different biological behavior oral cavity with a high grade of local invasion and metastasis to the cervical lymph nodes .
In addition, some evidence showed differences in prognostic significance of TILs depending on the tumor compartments (tumor epithelium, tumor stroma). For instance, in HPV-positive oropharyngeal squamous patients, stromal infiltration of CD8 T cells was associated with favorable outcome . Other studies suggested that a high level of CD8+ cells in tumor epithelium predicted a better clinical outcome . However, in a study conducted by Balermpas et. al the differences in the prognostic value of stromal and epithelial CD8+ cells has not been reported. It seems that more studies are needed to shed light on the role of CD8+ cells in different compartments of the tumor and their impact on cancer prognosis.
However, the advantage of CD4+ T cell infiltration in the tumor microenvironment is slightly controversial. At first, CD4+T cells were found as a positive prognostic factor in pancreatic and esophageal squamous cell carcinoma. In HNSCCs, studies suggested that high levels of tumor-infiltrating CD4+CD69+ T cells were positively correlated with more favorable prognosis [76, 82]. In contrast, other studies proposed CD4+T cells as a poor prognostic predictor, especially in oral cavity cancer . Heterogeneity of the CD4+T cell population and its characteristic cytokine profiles may explain these contradictory results .
In the microenvironment of many solid tumors, such as hepatocellular, breast and lung cancer, a high ratio of cytotoxic CD8+ T lymphocytes/Treg cells was reported as a good prognostic factor . However, the prognostic value of Treg cells seems to be different between types of cancer. Previous studies suggested that in HNSCC high immune-suppressing Treg cells number was associated with better prognosis and clinical outcome . In a study on the tumor specimens of oral cavity cancer patients, low stromal cytotoxic CD8+ T-lymphocyte counts and the high number of stromal Treg cells were associated with low survival . Some studies on oropharynx cancer showed different results compared with other types of head and neck cancers [87-89]. The data show that in oropharyngeal cancer high levels of cytotoxic CD8+ T cells could be considered as a positive prognostic factor, but the influence of high rate of T regulatory cells is controversial. According to this, more studies are required to confirm the prognostic value of the CD8+ T lymphocytes/Treg cells ratio in HNSCC.
Most former studies have focused on cytotoxic T cells that exhibit the highest antitumor activity among other immune cells. Recently B cells, another important fraction of TILs, have been identified as the important predictor of disease outcome [90-92]. Evidence shows that B cells can promote or inhibit the progression of tumors through producing antibodies against the tumor antigens, acting as APC and secreting numerous cytokines. Several factors such as tumor type and the subset of B cell influence the role of B cells in the support or prevention of tumor growth.
Most previous studies in HNSCC have investigated B cells by immunohistochemistry method that prognostic effect of tumor-infiltrating CD20+ B cells was described on the outcome [93, 94]. Distel et.al showed a favorable outcome correlated in the high percentage of B-lymphocytes in patients with early-stage HNSCC, in contrast to an inverse association in the advanced stage. These results suggest that there is phenotypic and functional plasticity of B cells during the course of disease progression . However knowledge about the different B cell subsets in tumor microenvironment of HNSCC is in short, recent study of flow cytometric analysis of tumor-infiltrating B cell subpopulations including activated (CD86+), antigen-presenting (CD86+CD21−), memory (IgD−CD27+) in HNSCC demonstrated significant difference in the frequencies of different B cell subsets in tumor microenvironment of patients with HPV+ compared to HPV- HNSCC although it did not show any relation to disease stage .
Besides, in some few studies infiltration of HNSCC by regulatory B cells was investigated. Lechner et. al observed the high infiltration of CD24hiCD38hi and CD25hi regulatory B cells in tumor tissue of HNSCC compared to peripheral blood of patients and healthy controls . However, the significance of regulatory B cells in immunity against tumor remains to be elusive in humans. In tongue squamous cell carcinoma has been indicated that CD19+IL-10+ regulatory B cells affected the survival of patients by inducing Tregs through secretion of IL-10 . Still, further investigation is required to clarify in more detail function and phenotype of regulatory B cell subsets in the tumor microenvironment of HNSCC.
Immune-inflamed cancer phenotype and benefit to immunotherapy
Like other solid tumors, HNSCC shows two main immunophenotypes: i) inflamed tumor type with a rich T cell infiltrate, a type 1 interferon signature, and various chemokine profiles, ii) non-inflamed type without these structures. The structure of T cell- inflamed tumor indicated a previous anti-tumor immune response might have existed that was ineffective due to the obstruction of tumor penetration through stroma or by the retention of immune cells in the stroma . Understanding the resistance mechanisms in both T cell–inflamed and non-inflamed tumors are essential for overcoming treatment failure and increasing the response rate of patients to current immunotherapy. In addition, the modulation of the tumor microenvironment has become increasingly an issue in the field of immunization, and studies on immune checkpoint mediated immunosuppression and cancer immunotherapy have peaked the safety of cancer treatment.
The new mAbs approved by the US Food and Drug Administration (FDA) for HNSCC patients are anti-PD-1 mAbs nivolumab and pembrolizumab, in addition to cetuximab, a mAb against epidermal growth factor receptor (EGFR). However, most do not benefit from anti-PD1 therapy. Understanding of Inhibitory checkpoint receptor mechanisms may help the clinician to correctly select certain immunotherapy options for specific patients. Some immune checkpoints such as LAG3 and TIM3have become attractive goals for prevailing to the resistance of tumors with an inflamed phenotype including melanoma, NSCLC, and HNSCC . Due to the potentially severe toxicity and high costs of immune checkpoint inhibitors, the search for predictive biomarkers that can target immune cell infiltration is highly demanded. The immune cell subsets and their position in the TME could affect the prognosis and prediction of response to Immune-checkpoint inhibitors therapy. Besides, Most clinical trials in both recurrent and metastatic HNSCC patients indicated that factors other than PD-L1 expression, including tumor-immune cell infiltration, tumor mutational burden and human papillomavirus (HPV) may contribute to the patients' response to treatment [63, 104].
Taken together, a better understanding of the tumor–immune cell cross talk and the resistance mechanisms in both T cell–inflamed and non-inflamed tumors, affect the successfulness of immunotherapy for overcoming resistance to available therapies and designing novel immunotherapies in order to increase patients benefit from immunotherapy.
In conclusion, HNSCC tumor microenvironment is composed of stromal fibroblasts, vasculature, immune cells, cytokines, and hypoxia which play a supportive role in the initiation, progression, and metastasis of the tumor. In HNSCC, there is a complexity in tumor-immune system interactions which are mainly dictated by the tumor microenvironment. A rational approach to further clinical investigation requires a deeper understanding of the interaction of the immune system with the tumor microenvironment. As more is discovered about the interaction of the immune system with HNSCC tumors in the development of the disease and in the mechanisms of tumor resistance; the opportunity for earlier intervention may also become possible.
- Head and Neck Squamous Cell Carcinoma: Update on Epidemiology, Diagnosis, and Treatment Marur Shanthi, Forastiere Arlene A.. Mayo Clinic Proceedings.2016;91(3). CrossRef
- Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer Ang K. Kian, Harris Jonathan, Wheeler Richard, Weber Randal, Rosenthal David I., Nguyen-Tân Phuc Felix, Westra William H., Chung Christine H., Jordan Richard C., Lu Charles, Kim Harold, Axelrod Rita, Silverman C. Craig, Redmond Kevin P., Gillison Maura L.. New England Journal of Medicine.2010;363(1). CrossRef
- Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial Posner M. R., Lorch J. H., Goloubeva O., Tan M., Schumaker L. M., Sarlis N. J., Haddad R. I., Cullen K. J.. Annals of Oncology.2011;22(5). CrossRef
- Prognostic Significance of p16INK4Aand Human Papillomavirus in Patients With Oropharyngeal Cancer Treated on TROG 02.02 Phase III Trial Rischin Danny, Young Richard J., Fisher Richard, Fox Stephen B., Le Quynh-Thu, Peters Lester J., Solomon Ben, Choi Jimin, O'Sullivan Brian, Kenny Lizbeth M., McArthur Grant A.. Journal of Clinical Oncology.2010;28(27). CrossRef
- The role of human papillomavirus in nongenital cancers Zandberg Dan P., Bhargava Ranjana, Badin Simon, Cullen Kevin J.. CA: A Cancer Journal for Clinicians.2012;63(1). CrossRef
- Risk factors for developing synchronous esophageal neoplasia in patients with head and neck cancer Wang Wen-Lun, Lee Ching-Tai, Lee Yi-Chia, Hwang Tzer-Zen, Wang Chih-Chun, Hwang Jau-Chung, Tai Chi-Ming, Chang Chi-Yang, Tsai Shang-Shyue, Wang Cheng-Ping, Ko Jenq-Yuh, Lin Jaw-Town. Head & Neck.2011;33(1). CrossRef
- Predictors of locoregional recurrence in early stage oral cavity cancer with free surgical margins Huang Tsai-Ying, Hsu Lee-Ping, Wen Yu-Hsuan, Huang Tung-Tsun, Chou Yu-Fu, Lee Chia-Fong, Yang Miao-Chun, Chang Yi-Kuo, Chen Peir-Rong. Oral Oncology.2010;46(1). CrossRef
- Tumor Microenvironment in Head and Neck Squamous Cell Carcinoma Curry Joseph M., Sprandio John, Cognetti David, Luginbuhl Adam, Bar-ad Voichita, Pribitkin Edmund, Tuluc Madalina. Seminars in Oncology.2014;41(2). CrossRef
- Effector CD4 and CD8 T Cells and Their Role in the Tumor Microenvironment Hadrup Sine, Donia Marco, thor Straten Per. Cancer Microenvironment.2012;6(2). CrossRef
- Peripheral blood monocyte and T-lymphocyte activation levels at diagnosis predict long-term survival in head and neck squamous cell carcinoma patients Aarstad Hans Jørgen, Vintermyr Olav K., Ulvestad Elling, Aarstad Helene H., Kross Kenneth W., Heimdal John. H.. APMIS.2015;123(4). CrossRef
- Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer Hartmann E, Wollenberg B, Rothenfusser S, Wagner M, Wellisch D, Mack B. Cancer research.2003;63(19):6478-87.
- Cytokines in head and neck cancer PRIES R, WOLLENBERG B. Cytokine & Growth Factor Reviews.2006;17(3). CrossRef
- Immune complexes, serum proteins, cell-mediated immunity, and immune regulation in patients with squamous cell carcinoma of the head and neck Veltri RW, Rodman SM, Maxim PE, Baseler MW, Sprinkle PM. Cancer.1986;57(12):2295-308.
- Clinical relevance of immune parameters in the tumor microenvironment of head and neck cancers Wallis Sebastian P., Stafford Nicholas D., Greenman John. Head & Neck.2014;37(3). CrossRef
- Down-regulation of ?-chain expression in T cells: a biomarker of prognosis in cancer? Whiteside TheresaL.. Cancer Immunology, Immunotherapy.2004;53(10). CrossRef
- New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape Mittal Deepak, Gubin Matthew M, Schreiber Robert D, Smyth Mark J. Current Opinion in Immunology.2014;27. CrossRef
- Cancer Immunoediting: Integrating Immunity's Roles in Cancer Suppression and Promotion Schreiber R. D., Old L. J., Smyth M. J.. Science.2011;331(6024). CrossRef
- The hypoxic tumor microenvironment: A driving force for breast cancer progression Semenza Gregg L.. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.2016;1863(3). CrossRef
- Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment Lee Esak, Pandey Niranjan B., Popel Aleksander S.. Expert Reviews in Molecular Medicine.2015;17. CrossRef
- Immune Suppression in Head and Neck Cancers: A Review Duray Anaëlle, Demoulin Stéphanie, Hubert Pascale, Delvenne Philippe, Saussez Sven. Clinical and Developmental Immunology.2010;2010. CrossRef
- Defects in the Human Leukocyte Antigen Class I Antigen Processing Machinery in Head and Neck Squamous Cell Carcinoma: Association with Clinical Outcome Meissner M.. Clinical Cancer Research.2005;11(7). CrossRef
- Protective mechanisms of head and neck squamous cell carcinomas from immune assault Young M. Rita I.. Head & Neck.2006;28(5). CrossRef
- Tumor-derived microvesicles in sera of patients with head and neck cancer and their role in tumor progression Bergmann Christoph, Strauss Laura, Wieckowski Eva, Czystowska Malgorzata, Albers Andreas, Wang Yun, Zeidler Reinhard, Lang Stephan, Whiteside Theresa L.. Head & Neck.2009;31(3). CrossRef
- Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes Kim JW, Wieckowski E, Taylor DD, Reichert TE, Watkins S, Whiteside TL. Clinical cancer research : an official journal of the American Association for Cancer Research.2005;11(3):1010-20.
- T-Regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis Facciabene A., Motz G. T., Coukos G.. Cancer Research.2012;72(9). CrossRef
- Differential macrophage programming in the tumor microenvironment Ruffell Brian, Affara Nesrine I., Coussens Lisa M.. Trends in Immunology.2012;33(3). CrossRef
- Exosomes and Cancer: A Newly Described Pathway of Immune Suppression Zhang H.-G., Grizzle W. E.. Clinical Cancer Research.2011;17(5). CrossRef
- Detection of Exosomal miRNAs in the Plasma of Melanoma Patients Pfeffer Susan, Grossmann Kenneth, Cassidy Pamela, Yang Chuan, Fan Meiyun, Kopelovich Levy, Leachman Sancy, Pfeffer Lawrence. Journal of Clinical Medicine.2015;4(12). CrossRef
- Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers Skog Johan, Würdinger Tom, van Rijn Sjoerd, Meijer Dimphna H., Gainche Laura, Curry William T., Carter Bob S., Krichevsky Anna M., Breakefield Xandra O.. Nature Cell Biology.2008;10(12). CrossRef
- Investigation of the roles of exosomes in colorectal cancer liver metastasis WANG XIA, DING XIAOLING, NAN LIJUAN, WANG YITING, WANG JING, YAN ZHIQIANG, ZHANG WEI, SUN JIHONG, ZHU WEI, NI BING, DONG SUZHEN, YU LEI. Oncology Reports.2015;33(5). CrossRef
- Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma Sohn Won, Kim Jonghwa, Kang So Hee, Yang Se Ra, Cho Ju-Yeon, Cho Hyun Chin, Shim Sang Goon, Paik Yong-Han. Experimental & Molecular Medicine.2015;47(9). CrossRef
- Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis Abusamra Ashraf J., Zhong Zhaohui, Zheng Xiufen, Li Mu, Ichim Thomas E., Chin Joseph L., Min Wei-Ping. Blood Cells, Molecules, and Diseases.2005;35(2). CrossRef
- Human Colorectal Cancer Cells Induce T-Cell Death Through Release of Proapoptotic Microvesicles: Role in Immune Escape Huber Veronica, Fais Stefano, Iero Manuela, Lugini Luana, Canese Paola, Squarcina Paola, Zaccheddu Annamaria, Colone Marisa, Arancia Giuseppe, Gentile Massimo, Seregni Ettore, Valenti Roberta, Ballabio Giuseppina, Belli Filiberto, Leo Ermanno, Parmiani Giorgio, Rivoltini Licia. Gastroenterology.2005;128(7). CrossRef
- The human melanoma cell line MelJuSo secretes bioactive FasL and APO2L/TRAIL on the surface of microvesicles. Possible contribution to tumor counterattack Martı́nez-Lorenzo Marı́a José, Anel Alberto, Alava Marı́a A, Piñeiro Andrés, Naval Javier, Lasierra Pilar, Larrad Luis. Experimental Cell Research.2004;295(2). CrossRef
- The role of cbl family of ubiquitin ligases in gastric cancer exosome-induced apoptosis of Jurkat T cells Qu Jing-Lei, Qu Xiu-Juan, Qu Jing-Lei, Qu Xiu-Juan, Zhao Ming-Fang, Teng Yue-E, Zhang Ye, Hou Ke-Zuo, Jiang You-Hong, Yang Xiang-Hong, Liu Yun-Peng. Acta Oncologica.2009;48(8). CrossRef
- Suppression of Lymphocyte Functions by Plasma Exosomes Correlates with Disease Activity in Patients with Head and Neck Cancer Ludwig Sonja, Floros Theofanis, Theodoraki Marie-Nicole, Hong Chang-Sook, Jackson Edwin K., Lang Stephan, Whiteside Theresa L.. Clinical Cancer Research.2017;23(16). CrossRef
- Clinical Significance of PD-L1+Exosomes in Plasma of Head and Neck Cancer Patients Theodoraki Marie-Nicole, Yerneni Saigopalakrishna S., Hoffmann Thomas K., Gooding William E., Whiteside Theresa L.. Clinical Cancer Research.2017;24(4). CrossRef
- Morphological and molecular features of oral fluid-derived exosomes: oral cancer patients versus healthy individuals Zlotogorski-Hurvitz Ayelet, Dayan Dan, Chaushu Gavriel, Salo Tuula, Vered Marilena. Journal of Cancer Research and Clinical Oncology.2015;142(1). CrossRef
- Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype Li Ling, Li Chao, Wang Shaoxin, Wang Zhaohui, Jiang Jian, Wang Wei, Li Xiaoxia, Chen Jin, Liu Kun, Li Chunhua, Zhu Guiquan. Cancer Research.2016;76(7). CrossRef
- Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck Brizel David M., Sibley Gregory S., Prosnitz Leonard R., Scher Richard L., Dewhirst Mark W.. International Journal of Radiation Oncology*Biology*Physics.1997;38(2). CrossRef
- Hypoxia-inducible Factor 1α and Antiangiogenic Activity of Farnesyltransferase Inhibitor SCH66336 in Human Aerodigestive Tract Cancer Han Ji-Youn, Oh Seung Hyun, Morgillo Floriana, Myers Jeffrey N., Kim Edward, Hong Waun Ki, Lee Ho-Young. JNCI: Journal of the National Cancer Institute.2005;97(17). CrossRef
- Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy Semenza Gregg L.. Trends in Pharmacological Sciences.2012;33(4). CrossRef
- Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes Lukashev D, Klebanov B, Kojima H, Grinberg A, Ohta A, Berenfeld L, et al . Journal of immunology.2006;177(8):4962-5.
- Mechanisms of Hypoxia-Mediated Immune Escape in Cancer Barsoum Ivraym B., Koti Madhuri, Siemens D. Robert, Graham Charles H.. Cancer Research.2014;74(24). CrossRef
- HIF-1alpha is a prognostic marker in oral squamous cell carcinomas Eckert AW, Schutze A, Lautner MH, Taubert H, Schubert J, Bilkenroth U. The International journal of biological markers.2010;25(2):87-92.
- Hypoxic tumor microenvironment of head and neck cancers downregulates Kv1. 3 channels in tumor infiltrating lymphocytes Chimote AA, Hajdu P, Sfyris AM, Casper KA, Conforti L. Am Assoc Immnol.2016.
- Characterization of the evolution of immune phenotype during the development and progression of squamous cell carcinoma of the head and neck De Costa Anna-Maria A., Schuyler Corinne A., Walker David D., Young M. Rita I.. Cancer Immunology, Immunotherapy.2011;61(6). CrossRef
- Effect of the Premalignant and Tumor Microenvironment on Immune Cell Cytokine Production in Head and Neck Cancer Johnson Sara, De Costa Anna-Maria, Young M.. Cancers.2014;6(2). CrossRef
- Interleukin-6 predicts recurrence and survival among head and neck cancer patients Duffy Sonia A., Taylor Jeremy M.G., Terrell Jeffrey E., Islam Mozaffarul, Li Yun, Fowler Karen E., Wolf Gregory T., Teknos Theodoros N.. Cancer.2008;113(4). CrossRef
- Increased prevalence of interleukin-17-producing CD4+ tumor infiltrating lymphocytes in human oral squamous cell carcinoma Lee Jang-Jaer, Chang Yen-Liang, Lai Wan-Ling, Ko Jenq-Yuh, Kuo Mark Yen-Ping, Chiang Chun-Pin, Azuma Miyuki, Chen Ching-Wen, Chia Jean-San. Head & Neck.2010;33(9). CrossRef
- A Unique Subset of CD4+CD25highFoxp3+ T Cells Secreting Interleukin-10 and Transforming Growth Factor- 1 Mediates Suppression in the Tumor Microenvironment Strauss L., Bergmann C., Szczepanski M., Gooding W., Johnson J. T., Whiteside T. L.. Clinical Cancer Research.2007;13(15). CrossRef
- Lymphocyte Subpopulations Infiltrating Squamous Carcinomas of the Head and Neck: Correlations with Extent of Tumor and Prognosis Wolf Gregory T., Hudson Jerry L., Peterson Karen A., Miller Harriet L., Mcclatchey Kenneth D.. Otolaryngology–Head and Neck Surgery.1986;95(2). CrossRef
- The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis Gooden M J M, de Bock G H, Leffers N, Daemen T, Nijman H W. British Journal of Cancer.2011;105(1). CrossRef
- Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer Balermpas P, Michel Y, Wagenblast J, Seitz O, Weiss C, Rödel F, Rödel C, Fokas E. British Journal of Cancer.2013;110(2). CrossRef
- Tumor Infiltrating CD8+ and Foxp3+ Lymphocytes Correlate to Clinical Outcome and Human Papillomavirus (HPV) Status in Tonsillar Cancer Näsman Anders, Romanitan Mircea, Nordfors Cecilia, Grün Nathalie, Johansson Hemming, Hammarstedt Lalle, Marklund Linda, Munck-Wikland Eva, Dalianis Tina, Ramqvist Torbjörn. PLoS ONE.2012;7(6). CrossRef
- CD8+ tumour-infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: A multicentre study of the German cancer consortium radiation oncology group (DKTK-ROG) Balermpas Panagiotis, Rödel Franz, Rödel Claus, Krause Mechthild, Linge Annett, Lohaus Fabian, Baumann Michael, Tinhofer Inge, Budach Volker, Gkika Eleni, Stuschke Martin, Avlar Melanie, Grosu Anca-Lidia, Abdollahi Amir, Debus Jürgen, Bayer Christine, Stangl Stefan, Belka Claus, Pigorsch Steffi, Multhoff Gabriele, Combs Stephanie E., Mönnich David, Zips Daniel, Fokas Emmanouil. International Journal of Cancer.2015;138(1). CrossRef
- Antitumor Activity of Human Papillomavirus Type 16 E7–Specific T Cells against Virally Infected Squamous Cell Carcinoma of the Head and Neck Albers Andreas, Abe Koji, Hunt Jennifer, Wang Jun, Lopez-Albaitero Andres, Schaefer Carsten, Gooding William, Whiteside Theresa L., Ferrone Soldano, DeLeo Albert, Ferris Robert L.. Cancer Research.2005;65(23). CrossRef
- Human Leukocyte Antigen (HLA) Class I Defects in Head and Neck Cancer: Molecular Mechanisms and Clinical Significance Ferris Robert L., Hunt Jennifer L., Ferrone Soldano. Immunologic Research.2005;33(2). CrossRef
- Multiplexed Analysis of Serum Cytokines as Biomarkers in Squamous Cell Carcinoma of the Head and Neck Patients Hathaway Bridget, Landsittel Douglas P., Gooding William, Whiteside Theresa L., Grandis Jennifer R., Siegfried Jill M., Bigbee William L., Ferris Robert L.. The Laryngoscope.2005;115(3). CrossRef
- Targeting the immune system: novel therapeutic approaches in squamous cell carcinoma of the head and neck Hoffmann Thomas K., Bier Henning, Whiteside Theresa L.. Cancer Immunology, Immunotherapy.2004;53(12). CrossRef
- Role of Antigen-Processing Machinery in the In Vitro Resistance of Squamous Cell Carcinoma of the Head and Neck Cells to Recognition by CTL López-Albaitero Andrés, Nayak Jayakar V., Ogino Takeshi, Machandia Avinash, Gooding William, DeLeo Albert B., Ferrone Soldano, Ferris Robert L.. The Journal of Immunology.2006;176(6). CrossRef
- Increased prevalence of tumour infiltrating immune cells in oropharyngeal tumours in comparison to other subsites: relationship to peripheral immunity Green Victoria L., Michno Anna, Stafford Nicholas D., Greenman John. Cancer Immunology, Immunotherapy.2013;62(5). CrossRef
- The head and neck cancer immune landscape and its immunotherapeutic implications Mandal Rajarsi, Şenbabaoğlu Yasin, Desrichard Alexis, Havel Jonathan J., Dalin Martin G., Riaz Nadeem, Lee Ken-Wing, Ganly Ian, Hakimi A. Ari, Chan Timothy A., Morris Luc G.T.. JCI Insight.2016;1(17). CrossRef
- The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis de Ruiter Emma J., Ooft Marc L., Devriese Lot A., Willems Stefan M.. OncoImmunology.2017;6(11). CrossRef
- CD4 T-cell Subsets and Tumor Immunity: The Helpful and the Not-so-Helpful Kim H.-J., Cantor H.. Cancer Immunology Research.2014;2(2). CrossRef
- Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo Nishimura T, Iwakabe K, Sekimoto M, Ohmi Y, Yahata T, Nakui M, et al . The Journal of experimental medicine.1999;190(5):617-27.
- Increase in immune cell infiltration with progression of oral epithelium from hyperkeratosis to dysplasia and carcinoma Gannot G, Gannot I, Vered H, Buchner A, Keisari Y. British journal of cancer.2002;86(9):1444-8.
- Overexpression of Transforming Growth Factor β1 in Head and Neck Epithelia Results in Inflammation, Angiogenesis, and Epithelial Hyperproliferation Lu Shi-Long, Reh Douglas, Li Allen G., Woods Jennifer, Corless Christopher L., Kulesz-Martin Molly, Wang Xiao-Jing. Cancer Research.2004;64(13). CrossRef
- CD8+ Tumor-Infiltrating Lymphocytes Together with CD4+ Tumor-Infiltrating Lymphocytes and Dendritic Cells Improve the Prognosis of Patients with Pancreatic Adenocarcinoma Fukunaga Akira, Miyamoto Masaki, Cho Yasushi, Murakami Soichi, Kawarada You, Oshikiri Taro, Kato Kentaro, Kurokawa Takanori, Suzuoki Masato, Nakakubo Yoshihiro, Hiraoka Kei, Itoh Tomoo, Morikawa Toshiaki, Okushiba Shunichi, Kondo Satoshi, Katoh Hiroyuki. Pancreas.2004;28(1). CrossRef
- Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome Galon J.. Science.2006;313(5795). CrossRef
- Predominant infiltration of macrophages and CD8+T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer Kawai Osamu, Ishii Genichiro, Kubota Kaoru, Murata Yukinori, Naito Yoichi, Mizuno Tetsuya, Aokage Keiju, Saijo Nagahiro, Nishiwaki Yutaka, Gemma Akihiko, Kudoh Syoji, Ochiai Atsushi. Cancer.2008;113(6). CrossRef
- Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, et al . Cancer research.2001;61(13):5132-6.
- Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer Sato E., Olson S. H., Ahn J., Bundy B., Nishikawa H., Qian F., Jungbluth A. A., Frosina D., Gnjatic S., Ambrosone C., Kepner J., Odunsi T., Ritter G., Lele S., Chen Y.-T., Ohtani H., Old L. J., Odunsi K.. Proceedings of the National Academy of Sciences.2005;102(51). CrossRef
- CD8+ and CD4+ tumour infiltrating lymphocytes in relation to human papillomavirus status and clinical outcome in tonsillar and base of tongue squamous cell carcinoma Nordfors Cecilia, Grün Nathalie, Tertipis Nikolaos, Ährlund-Richter Andreas, Haeggblom Linnea, Sivars Lars, Du Juan, Nyberg Tommy, Marklund Linda, Munck-Wikland Eva, Näsman Anders, Ramqvist Torbjörn, Dalianis Tina. European Journal of Cancer.2013;49(11). CrossRef
- Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma Pretscher Dominik, Distel Luitpold V, Grabenbauer Gerhard G, Wittlinger Michael, Buettner Maike, Niedobitek Gerald. BMC Cancer.2009;9(1). CrossRef
- Prognostic Value of Tumor-Infiltrating CD4+ T-Cell Subpopulations in Head and Neck Cancers Badoual C.. Clinical Cancer Research.2006;12(2). CrossRef
- Radiochemotherapy induces a favourable tumour infiltrating inflammatory cell profile in head and neck cancer Tabachnyk M., Distel L.V.R., Büttner M., Grabenbauer G.G., Nkenke E., Fietkau R., Lubgan D.. Oral Oncology.2012;48(7). CrossRef
- Differential infiltration of CD8+and NK cells in lip and oral cavity squamous cell carcinoma Zancope E., Costa N. L., Junqueira-Kipnis A. P., Valadares M. C., Silva T. A., Leles C. R., Mendonça E. F., Batista A. C.. Journal of Oral Pathology & Medicine.2010;39(2). CrossRef
- Tumor infiltrating lymphocytes (TIL) and prognosis in oral cavity squamous carcinoma: A preliminary study Wolf Gregory T., Chepeha Douglas B., Bellile Emily, Nguyen Ariane, Thomas Daffyd, McHugh Jonathan. Oral Oncology.2015;51(1). CrossRef
- Oral squamous cell carcinoma: Review of prognostic and predictive factors Massano João, Regateiro Frederico S., Januário Gustavo, Ferreira Artur. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology.2006;102(1). CrossRef
- Stromal infiltration of CD8 T cells is associated with improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma Oguejiofor K, Hall J, Slater C, Betts G, Hall G, Slevin N, Dovedi S, Stern P L, West C M L. British Journal of Cancer.2015;113(6). CrossRef
- Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in head and neck cancers Uppaluri R, Dunn GP, Lewis JS. Cancer immunity.2008;8:16.
- T regulatory cell markers in oral squamous cell carcinoma: Relationship with survival and tumor aggressiveness MOREIRA GEANE, FULGÊNCIO LÍVIA BONFIM, DE MENDONÇA ELISMAURO FRANCISCO, LELES CLÁUDIO RODRIGUES, BATISTA ALINE CARVALHO, DA SILVA TARCÍLIA APARECIDA. Oncology Letters.2010;1(1). CrossRef
- Heterogeneity of human effector CD4+ T cells Annunziato Francesco, Romagnani Sergio. Arthritis Research & Therapy.2009;11(6). CrossRef
- Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis Shang Bin, Liu Yao, Jiang Shu-juan, Liu Yi. Scientific Reports.2015;5(1). CrossRef
- Tumor-infiltrating lymphocytes, particularly the balance between CD8+ T cells and CCR4+ regulatory T cells, affect the survival of patients with oral squamous cell carcinoma Watanabe Yoshiko, Katou Fuminori, Ohtani Haruo, Nakayama Takashi, Yoshie Osamu, Hashimoto Kenji. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology.2010;109(5). CrossRef
- Infiltrating lymphocytes and human papillomavirus-16-associated oropharyngeal cancer Wansom Derrick, Light Emily, Thomas Dafydd, Worden Francis, Prince Mark, Urba Susan, Chepeha Douglas, Kumar Bhavna, Cordell Kitrina, Eisbruch Avraham, Taylor Jeremy, Moyer Jeffrey, Bradford Carol, D'Silva Nisha, Carey Thomas, McHugh Jonathan, Wolf Gregory. The Laryngoscope.2011;122(1). CrossRef
- Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer Ward M J, Thirdborough S M, Mellows T, Riley C, Harris S, Suchak K, Webb A, Hampton C, Patel N N, Randall C J, Cox H J, Jogai S, Primrose J, Piper K, Ottensmeier C H, King E V, Thomas G J. British Journal of Cancer.2013;110(2). CrossRef
- Prognostic Value of CD25 Expression on Lymphocytes and Tumor Cells in Squamous-Cell Carcinoma of the Head and Neck Loose David, Signore Alberto, Bonanno Elena, Vermeersch Hubert, Dierckx Rudi, Deron Philippe, Van de Wiele Christophe. Cancer Biotherapy and Radiopharmaceuticals.2008;23(1). CrossRef
- Immunotype and Immunohistologic Characteristics of Tumor-Infiltrating Immune Cells Are Associated with Clinical Outcome in Metastatic Melanoma Erdag G., Schaefer J. T., Smolkin M. E., Deacon D. H., Shea S. M., Dengel L. T., Patterson J. W., Slingluff C. L.. Cancer Research.2012;72(5). CrossRef
- CD20+ Tumor-Infiltrating Lymphocytes Have an Atypical CD27- Memory Phenotype and Together with CD8+ T Cells Promote Favorable Prognosis in Ovarian Cancer Nielsen J. S., Sahota R. A., Milne K., Kost S. E., Nesslinger N. J., Watson P. H., Nelson B. H.. Clinical Cancer Research.2012;18(12). CrossRef
- Margin-Infiltrating CD20+ B Cells Display an Atypical Memory Phenotype and Correlate with Favorable Prognosis in Hepatocellular Carcinoma Shi J.-Y., Gao Q., Wang Z.-C., Zhou J., Wang X.-Y., Min Z.-H., Shi Y.-H., Shi G.-M., Ding Z.-B., Ke A.-W., Dai Z., Qiu S.-J., Song K., Fan J.. Clinical Cancer Research.2013;19(21). CrossRef
- Distribution and significance of interstitial fibrosis and stroma-infiltrating B cells in tongue squamous cell carcinoma LAO XIAO-MEI, LIANG YU-JIE, SU YU-XIONG, ZHANG SI-EN, ZHOU XI, LIAO GUI-QING. Oncology Letters.2016;11(3). CrossRef
- CD19+IL-10+ regulatory B cells affect survival of tongue squamous cell carcinoma patients and induce resting CD4+ T cells to CD4+Foxp3+ regulatory T cells Zhou Xi, Su Yu-Xiong, Lao Xiao-Mei, Liang Yu-Jie, Liao Gui-Qing. Oral Oncology.2016;53. CrossRef
- Tumour infiltrating lymphocytes in squamous cell carcinoma of the oro- and hypopharynx: Prognostic impact may depend on type of treatment and stage of disease Distel Luitpold V., Fickenscher Rainer, Dietel Katrin, Hung Alexander, Iro Heiner, Zenk Johannes, Nkenke Emeka, Büttner Maike, Niedobitek Gerald, Grabenbauer Gerhard G.. Oral Oncology.2009;45(10). CrossRef
- Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma Lechner Axel, Schlößer Hans A., Thelen Martin, Wennhold Kerstin, Rothschild Sacha I., Gilles Ramona, Quaas Alexander, Siefer Oliver G., Huebbers Christian U., Cukuroglu Engin, Göke Jonathan, Hillmer Axel, Gathof Birgit, Meyer Moritz F., Klussmann Jens P., Shimabukuro-Vornhagen Alexander, Theurich Sebastian, Beutner Dirk, von Bergwelt-Baildon Michael. OncoImmunology.2019;8(3). CrossRef
- Characterization of tumor-associated B cell subsets in head and neck squamous cell carcinoma. American Society of Clinical Oncology Rothschild S, Lechner A, Schloesser HA, Thelen M, Shimabukuro-Vornhagen A, Beutner D. American Society of Clinical Oncology.2015.
- Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck Hanna Glenn J., Liu Hongye, Jones Robert E., Bacay Alyssa F., Lizotte Patrick H., Ivanova Elena V., Bittinger Mark A., Cavanaugh Megan E., Rode Amanda J., Schoenfeld Jonathan D., Chau Nicole G., Haddad Robert I., Lorch Jochen H., Wong Kwok-Kin, Uppaluri Ravindra, Hammerman Peter S.. Oral Oncology.2017;67. CrossRef
- The STING pathway and the T cell-inflamed tumor microenvironment Woo Seng-Ryong, Corrales Leticia, Gajewski Thomas F.. Trends in Immunology.2015;36(4). CrossRef
- Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy Devaud Christel, John Liza B, Westwood Jennifer A, Darcy Phillip K, Kershaw Michael H. OncoImmunology.2013;2(8). CrossRef
- Immune Checkpoint Inhibition in Cancers that Affect the Head and Neck. International journal of radiation oncology, biology, physics Parameswaran J, Burtness B. International journal of radiation oncology, biology, physics.2017;98(5):969-73.
- Review of cetuximab in the treatment of squamous cell carcinoma of the head and neck Merlano M, Occelli M. Therapeutics and clinical risk management.2007;3(5):871-6.
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