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Abstract

Objectives

Research progress of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) based on immune microenvironment.

Methods

This article preliminarily discusses the composition of immune microenvironment components and immune therapy and elaborates and analyzes the involvement and impact of T cells, B cells, natural killer (NK) cells, tumor-associated fibroblasts, and bone marrow-derived suppressor cells in HPV-positive HNSCC on tumor progression and prognosis. Furthermore, the application of immune-related therapies in HPV-positive HNSCC is explored.

Results

It is found that immune microenvironment research plays an important role in the pathogenesis and treatment of HPV-positive HNSCC.

Conclusions

Immune microenvironment research as an important means to explore tumors has played an important role in the study of HPV-positive HNSCC. We describe the biological significance of important components of HNSCC immune microenvironment by analyzing the effects of HNSCC immune microenvironment components and immunotherapy on HPV-positive HNSCC. May to provide new strategies for experimental research and clinical prevention and treatment of this disease.

Keywords

HPV-positive head and neck squamous cell carcinoma tumor microenvironment immune therapy

Introduction

Head and neck squamous cell carcinoma (HNSCC) has a very complex immune microenvironment. In this review, we elaborate the involvement and impact of T cells, B cells, natural killer (NK) cells, tumor-associated fibroblasts, and bone marrow-derived suppressor cells in human papillomavirus (HPV)-positive HNSCC on tumor progression and prognosis. Furthermore, the application of immunotherapy in HPV-positive HNSCC is explored. We believe that various cells play different important roles in the immune microenvironment.

HNSCC is a group of heterogeneous tumors originating from the squamous epithelium of the oral cavity, oropharynx, larynx, and hypopharynx. There are more than 2.5 million cases globally, with over 370,000 deaths annually.^1,2 Many HNSCC patients present with locally advanced disease, often accompanied by significant lymph node involvement. The treatment usually involves a combination of surgery, radiotherapy, chemotherapy and immunotherapy. Patients’ 5-year overall survival rate is approximately 30–40%.³ In addition, the disease's special location greatly impairs the patients’ quality of life.

It has been confirmed that HNSCC is closely related to smoking and alcohol consumption. In South Asia and Central South Asia, oral squamous cell carcinoma is associated with a local form of smokeless tobacco, often leading to oral cancer and precancerous lesions.⁴ In addition to tobacco, betel nut chewing is an important carcinogen for oral squamous cell carcinoma. HPV infection is also considered a significant risk factor, accounting for 40–80% of HPV infections in cases of oropharyngeal squamous cell carcinoma in the United States.⁵ Approximately 50% of tonsil cancer is driven by HPV.⁶ HPV is a group of DNA viruses that can cause tumor formation. In 1976, Z-Hau discovered that these viruses may cause cervical cancer and subsequently identified that infection with HPV16 and HPV18 types is the leading cause of cervical cancer.⁷ His team also first demonstrated the presence of HPV in human tongue cancer.⁸ HPV can infect the cervix and oropharyngeal mucosa through minor abrasions and direct contact. HPV infection in HNSCC is mainly driven by HPV type 16 and rarely by other high-risk HPV types.⁹ In the past decade, HPV16 infection has been increasingly recognized as an essential factor in the pathogenesis of oral squamous cell carcinoma.^10,11

The tumor microenvironment (TME) consists of different cellular components, including endothelial cells, immune cells, and fibroblasts. Endothelial cells play an important role in tumor angiogenesis, providing nutritional support for tumor growth and development.¹² Immune cells, including granulocytes, lymphocytes, and macrophages, participate in various immune reactions, such as tumor cell escape, immune suppression, and immune response.¹³ Fibroblasts play a crucial role in tumor metastasis by providing reliable channels for endothelial cell angiogenesis in the tumor.¹⁴ Currently, it is widely accepted that although TME is composed of different cell subpopulations such as cancer-associated stromal fibroblasts, T cells, B cells, neutrophils, macrophages, myeloid-derived suppressor cells (MDSCs), NK cells, and mast cells, the composition and structure of TME vary depending on the type of cancer and the patient.^15,16 The main problem in HNSCC treatment is its high recurrence or metastasis rate, which may be attributed to its substantial heterogeneity.¹⁷ The host immune system can recognize and eliminate tumor cells. However, studies have shown that HNSCC not only evades recognition by immune cells but also possesses immune-suppressive effects.¹⁸ It has been reported that this immune evasion is achieved by downregulating the expression of human leukocyte antigens, which in turn impairs the recognition of cancer cells by T cells.¹⁹ In order to further understand the impact of HPV infection on HNSCC, the following will briefly discuss the tumor immune microenvironment.

Cell type

T cells

T cells are an important component of the adaptive immune system and show more potent immune responses in HPV-positive HNSCC.²⁰ T cells can be divided into CD4+ T cells and CD8+ T cells, which kill tumor cells by producing granzymes or secreting cytokines activated by CD4+ T and CD8+ T cells.²¹ Programmed death-1 (PD-1) is a co-inhibitory receptor expressed on activated CD4+ T and CD8+ T cells. PD-1 includes two ligands, PD-L1 and PD-L2,²² and the levels of PD-1 are upregulated in CD4+ T and CD8+ T cells in various types of cancer.²³ The expression of PD-L1 detected in extracellular vesicles isolated from plasma samples of HNSCC patients is associated with disease progression.²⁴ Research has found that high levels of CD4+ T cells are significantly associated with better overall survival compared to low levels of CD4+ T infiltration in HPV-positive HNSCC patients.²⁵ Similarly, other studies have confirmed the correlation between CD4+ T and CD8+ T cell infiltration and better overall survival.^26,27 These data confirm the critical role of T cell infiltration in the prognosis of HPV-positive HNSCC patients and suggest that low levels of intratumoral CD4+ T cells in advanced stages of HNSCC may be a breakthrough for tumor immunotherapy.²⁸ A study found that HPV-positive HNSCC patients produce more immunogenic antigens than HPV-negative patients by analyzing of CD4+ T and CD8+ T cells.²⁹ The infiltration of CD8+ T cells in HPV-positive HNSCC patients has significant differences in immune prognosis between high-risk and low-risk patients as revealed by RNA sequencing, providing evidence for the limited response of immune checkpoint inhibitors in HPV-positive HNSCC patients.³⁰ In a study of sinonasal squamous cell carcinoma,³¹ differences in the immune cell population in the TME were found, including higher levels of T cells, dysfunctional CD8+ T cells, and overall immune cell infiltration in HPV-positive sinonasal squamous cell carcinoma. The mechanism of CD8+ T cell dysfunction in HNSCC may be attributed to the elevated levels of helper T cell 17 (Th17) cells, which are possibly induced by increased release of interleukin-23 (IL-23) and interleukin-6 (IL-6) by HNSCC cells.^32,33

B cells

Increasing attention is being paid to the immune system's role in tumor development. Human B cells have multiple subgroups, including B cell precursors, immature B cells, plasma cells, memory B cells, and immune-suppressive or regulatory B cells.³⁴ B cells are mainly involved in humoral immune responses, and B cells and plasma cells in the TME can inhibit anti-tumor immunity through various mechanisms, with interleukin-10 (IL-10) being considered a major immunoregulatory factor.³⁵ Wieland conducted RNA-seq analysis on samples from HPV-positive HNSCC patients to identify transcriptional differences between subsets of B cells. Several antigen-specific B cell subgroups were found in the TME of patients, and these subgroups can inhibit anti-tumor immunity through various immune-regulatory proteins, including but not limited to transforming growth factor-beta (TGF-β), IL-10, and interleukin-35 (IL-35).^36,37 Recent studies have shown that antibodies produced by tumor-infiltrating B cells in the TME of HPV-positive HNSCC patients are specific to HPV viral antigens E2, E6, and E7. However, the role of these HPV-specific antibodies in anti-tumor responses is still under investigation.³⁸ Andreu proposed that B cells are involved in chronic inflammation, leading to the development of squamous cell carcinoma.³⁹ An early study on 33 HPV-positive HNSCC patients demonstrated that increased B cell infiltration in lymph node metastases can improve prognosis.⁴⁰ In a study investigating the infiltration of B cell subsets in HPV-related HNSCC and their correlation with prognosis,⁴¹ higher levels of B cell infiltration were found in HPV-positive HNSCC samples, and higher infiltration of B cells was associated with better prognosis. It was also found that high-density B lymphocytes were associated with CD4+ T lymphocytes in sinonasal squamous cell carcinoma. A study analyzed B cell subsets in the peripheral blood of HPV-positive HNSCC patients using flow cytometry and found that different immune infiltration patterns were related to serum tumor-associated antigen reactions and the presence of B cell subsets in HNSCC, indicating the involvement of B cell subsets in promoting tumor and anti-tumor activity.⁴²

Natural killer cells

In recent years, NK cells have been recognized for their role as innate immune effectors and as key components in modulating adaptive immunity. This is primarily due to the potent functional abilities of NK cells and their early secretion of gamma-interferon (IFN-γ), which activates effector cells of adaptive immunity, particularly Th1 cells and myeloid cells, helping shape the immune TME.^43,44 Mandal et al. analyzed the immune status of HPV-positive HNSCC using The Cancer Genome Atlas database and found high levels of CD56 NK cell infiltration in sinonasal squamous cell carcinoma. CD56 NK cell infiltration was associated with better survival rates in sinonasal squamous cell carcinoma and HNSCC, while tumors with smoking characteristics had lower immune infiltration and poorer survival rates.⁴⁵ Bochen et al. studied the relationship between vitamin D deficiency and the anti-tumor activity of NK cells in 463 HPV-positive HNSCC patients and found that vitamin D deficiency was more common in HNSCC patients and was associated with lymphatic metastasis, shorter overall survival, and changes in immune cell infiltration in the TME.⁴⁶ Further research suggests that vitamin D deficiency increases the cytotoxicity of NK cells against tumors, implying that appropriate vitamin D supplementation may improve patients’ prognosis by promoting anti-tumor immune responses. A study⁴⁷ found that lectin-like transcript 1, encoded by the CLEC2D gene and expressed in tumor cells, contributes to immune evasion and targets NK cell-mediated immunotherapy. By studying the expression of CLEC2D mRNA in HPV-infected head and neck tumors, it was found that the impact of CLEC2D expression on prognosis depended on the HPV status and different cancer types in oral squamous cell carcinoma. The model showed a significant correlation between CLEC2D expression and NK cell infiltration. Wagner et al.⁴⁸ identified CD56 + cells as mainly cytotoxic NK cells. It was found that the number of CD56 + cells was significantly higher in HPV-positive HNSCC patients than in HPV-negative HNSCC patients, and the presence of CD56 + cells was associated with a better prognosis in HPV-negative HNSCC.

Cancer-associated fibroblasts

Cancer-associated fibroblasts (CAFs) create a favorable environment for tumor development and account for more than 50% of stromal cells in tumors.⁴⁹ CAFs inhibit the function of immune cells through the secretion of various cytokines or metabolites and to promote tumor growth, invasion, and metastasis. CAFs also shape the tumor extracellular matrix, form a drug barrier, and prevent deep penetration of drugs and immune cells into tumor tissue, thereby reducing the effectiveness of tumor treatment. Wang et al.,⁵⁰ through analysis of clinical samples and public sequencing data, found that exosomes derived from HPV-positive HNSCC cells significantly reduced the phenotypic transformation of CAFs. It was demonstrated that lower CAF infiltration was associated with a better prognosis in HPV-positive HNSCC patients. Bezzecchi et al.⁵¹ used single-cell RNA-seq to analyze HPV-positive HNSCC patient samples and discovered the association between NF-YAs and CAFs. They suggested that overexpression of NF-YAs had a protective effect in HPV-positive HNSCC patients, and this protective effect was mainly limited to p53-mutated tumors and malignant incomplete epithelial-mesenchymal transition cells. Byers et al.⁵² proposed that clinical prognosis and recurrence probability in HNSCC patients could be predicted by studying the serum CAF profile. CAF spectrum analysis is a more practical for assessing tumor hypoxia than direct intratumoral measurement.

Myeloid-derived suppressor cells

MDSCs are pathologically activated neutrophils and monocytes with strong immunosuppressive activity, which regulate immune responses in many pathological conditions. Under normal circumstances, MDSCs can differentiate into dendritic cells, macrophages, and/or granulocytes. However, in certain pathological conditions such as tumors, inflammation, trauma, and autoimmune diseases, an expansion of MDSCs can be detected. Particularly in the peripheral blood and tumor tissue of cancer patients, there is a significant increase in the number and proportion of MDSCs associated with tumor size and malignancy.⁵³ MDSC expression has been found in human HNSCC samples and is positively correlated with PD-1 and PD-L1 expression.⁵⁴ Ma et al.⁵⁵ conducted a retrospective analysis and found that the number of MDSCs was significantly higher in HPV-positive HNSCC compared to the standard control group, suggesting that HPV infection may promote MDSC aggregation. By monitoring lncRNA expression between HPV-positive/negative nasopharyngeal squamous cell carcinoma and normal oral mucosa using an array, multiple gene expression levels were found to have a negative correlation with MDSC expression in HPV-positive nasopharyngeal carcinoma.

Immunotherapy

HNSCC, as a highly immune-infiltrated heterogeneous tumor, exhibits molecular heterogeneity due to cancer gene mutations, the immune composition of the TME, epigenetic changes, and chromosomal instability.⁵⁶ Moreover, different etiologies of HNSCC seem to utilize different immune escape mechanisms.^57,58 These characteristics of HNSCC pose significant challenges to treatment. Therefore, an ideal treatment approach needs to be personalized.⁵⁹ Over the years, immunotherapy has been at the forefront of cancer research. It has shown promising therapeutic benefits in various types of cancers, including HNSCC, becoming one of the vital treatment modalities.⁶⁰ Currently, the available immunotherapies for HNSCC are Nivolumab and Pembrolizumab, both PD-1 immune checkpoint inhibitors.⁶¹ However, increasing evidence suggests that HNSCC can escape the immune response from these two immunotherapies.⁶² One approach to overcome immune evasion is to target the known molecular pathways in HNSCC that are affected and associated specifically with its immune characteristics, focusing on three pathways: STAT3, PI3 K/AKT/mTOR, and Wnt pathways.⁶³ Recently, a study in HPV-positive HNSCC patients identified CD8+ T cell epitopes derived from the E2 immune target and detected a large number of E2-specific CD8+ T cells in the TME of such patients, demonstrating that E2 is a primary immunotherapeutic target.^64,65 Furthermore, the role of intracellular DNA sensor agonists in immune therapy has received increasing attention. Lu et al.⁶⁶ discovered a novel role of DNA sensor agonists in the carcinogenesis process of HPV-positive HNSCC patients, where activation of the DNA sensor agonist signaling pathway played an important role in the therapeutic monoclonal antibody treatment of HNSCC patients. Dorta et al.⁶⁷ found that combining α-PD-1 treatment with DNA sensor agonists could serve as a potential therapeutic approach for HPV-positive HNSCC patients, especially for relapsed patients who are ineffective with α-PD-1 monotherapy. The application of specific cytokines in immunotherapy has also been of interest. Luedke et al.⁶⁸ found enhanced extracellular signal-regulated kinase phosphorylation (critical for Fc receptor function) in cetuximab and IL-12 co-stimulated NK cells, suggesting that IL-12 may enhance the anti-tumor activity of cetuximab against HNSCC by activating the Fc receptor mechanism of NK cells, indicating that cytokine application may be an effective adjuvant for cetuximab treatment of HPV-positive HNSCC.

Research in the field of therapeutic vaccination is evolving each year, including HNSCC are in pre-clinical and clinical studies. At present, vaccine research on HNSCC has mainly focused on human papilloma virus, therapeutic vaccines against HPV-related antigens, therapeutic vaccines targeting non-viral antigens and combining immune therapies.⁶⁹ Although vaccine treatments hold great promise, but the two main challenges to personalized vaccines are manufacturing cost and patient accessibility. So we have to find a quick and effective treatment.⁷⁰

Prospects

The TME consists of various cell types and extracellular matrix components interacting with cancer cells, promoting cancer progression. During the process of tumor development, the tumor immune microenvironment includes but is not limited to macrophages, DCs, neutrophils, B cells, T cells, and CAFs. Cytokines such as IL-4, IL-5, IL-10, and TGF promote immune escape through specific mechanisms. In the immune process, tumor cells have also developed various mechanisms to counteract immune responses. CAFs are the most common cells in the TME, and the immune-suppressive features of CAFs in multiple tumors deserve further investigation.

The heterogeneity of the tumor immune microenvironment is the main reason for the differential efficacy of immunotherapy. When the immune system encounters foreign invasions, it mobilizes immune cells and initiates an inflammatory immune response. After eliminating the “invaders,” it activates immune suppression to prevent excessive inflammatory responses and maintain a microenvironment suitable for tissue damage repair. However, tumors exploit this adaptive immune mechanism by recruiting a large number of immune-suppressive cells within the tumor tissue, creating an immune-suppressive microenvironment. Due to individual differences, there are significant variations in the types and quantities of immune-suppressive cells recruited within tumors among different patients, leading to distinct TME states and rendering the same targeted therapy ineffective.

In recent years, with the application of technologies such as single-cell RNA sequencing (scRNA-seq), whole-exome sequencing, multiplex immunofluorescence, and mass cytometry, researchers have made further progress in studying the heterogeneity of the immune microenvironment in HNSCC. Through the analysis of HNSCC single-cell RNA-seq data, researchers have characterized HNSCC patients into different subgroups. Then, using the network topology to screen out key genes essential for HNSCC immune hot phenotypes, a neural network model is constructed through deep learning frameworks to predict the effectiveness of anti-PD-1/PD-L1 therapy. CXCL9, 10, 11, and CCL5 were identified as key genes that initiate and maintain the HNSCC immune hot phenotype, enhancing immune response and infiltration. It is believed that CXCL9-11 and CCL5 positively regulate immune cells and the immune cycle in HNSCC and can be used to predict the effect of anti-PD-1/PD-L1 therapy on HNSCC.

Due to the high heterogeneity of HPV-associated HNSCC and its complex immune microenvironment, although immunotherapy is receiving increasing attention and playing a significant role in improving overall patient survival rates, it is recognized that the current immunotherapeutic approaches are still far from sufficient for the diverse TME of HNSCC. Therefore, there is a need to discover more precise therapeutic targets and more effective signaling pathways to explore new treatment strategies.

Conclusion

HNSCC has a very complex immune microenvironment. We propose that T cells, B cells, NK cells, tumor-associated fibroblasts, and MDSCs play different important roles in the immune microenvironment of HPV-positive HNSCC. The application of immunotherapy in HPV-positive HNSCC is also diverse and has become an important treatment modality. By understanding the role of different components of immune microenvironment of HNSCC, it is helpful to further understand the mechanism of HNSCC.

Footnotes

Acknowledgements

We are grateful for the funding support provided by Professor Chen Min.

Author contributions

The authors confirm contribution to the paper as follows: article conception and design: Zhu Dong; data collection: He Xiang and Li Yu; analysis and interpretation of results: Li Guoping; draft manuscript preparation: Zhu Dong and Chen Min. All authors have read and agreed to the published version of the manuscript.

Data availability statement

It is not applicable to this article as no new data were created or analyzed in this study.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

Ethical approval is not applicable for this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the The Science and Technology Development Fund, Macau SAR, (grant number file No.:0114/2022/A).

ORCID iD

Dong Zhu

Statement of human and animal rights

This article does not contain any studies with human or animal subjects.

Statement of informed consent

There are no human subjects in this article and informed consent is not applicable.

Author biographies

Dong Zhu is a PhD candidate. His research area is otorhinolaryngology, focusing on the prevention and treatment of head and neck tumors.

Xiang He is a Doctor of Biomedical Sciences. His research area is respiratory diseases with an emphasis on allergy.

Yu Li is a Doctor of Medicine. His research areas are traditional Chinese medicine prescriptions and artificial intelligence research.

Guoping Li is an M.d., professor. His research area is respiratory diseases, with an emphasis on air pollution and allergic diseases.

Min Chen is a Doctor of Medicine. His research area is traditional Chinese acupuncture and health care.

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Immune microenvironment of human papillomavirus-positive head and neck squamous cell carcinoma

Abstract

Objectives

Methods

Results

Conclusions

Keywords

Introduction

Cell type

T cells

B cells

Natural killer cells

Cancer-associated fibroblasts

Myeloid-derived suppressor cells

Immunotherapy

Prospects

Conclusion

Footnotes

Acknowledgements

Author contributions

Data availability statement

Declaration of conflicting interests

Ethical approval

Funding

ORCID iD

Statement of human and animal rights

Statement of informed consent

Author biographies

References