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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Promising systemic immunotherapies in head and neck squamous cell carcinoma
Neil Gildener-Leapman1, Robert L Ferris, Julie E Bauman
1Department of Otolaryngology, University of Pittsburgh Eye and Ear Institute, 203 Lothrop Street, Pittsburgh, PA 15213, United States.
Abstract:
Patients with head and neck squamous cell carcinoma (HNSCC) demonstrate poor survival and significant treatment morbidity with standard therapy. The immune profile in HNSCC, whether caused by carcinogen exposure or human papillomavirus (HPV), is notably immunosuppressive. Early clinical trials of immunotherapy in HNSCC were troubled by systemic toxicity or difficulties in local administration. Now, interest in immunotherapy has been revitalized by mechanistic insights into immune evasion by HNSCC, coupled to ongoing development of novel immunotherapies. This review will summarize immune escape mechanisms in HNSCC, namely downregulation of tumor antigen (TA) presentation, aberrant regulation of the signal transducer and activator of transcription (STAT) family, the immunosuppressive cytokine milieu, and dysregulation of immune effector cells. Therapeutic strategies hypothesized to specifically counter HNSCC immunosuppression will then be discussed. We will survey TA- targeted monoclonal antibodies (mAb), including the prototype cetuximab, as well as adjunctive strategies to enhance antibody-dependent cell-mediated cytotoxicity. We will review immunomodulation to restore STAT1/STAT3 activation balance. Examples of mAb therapy to block immunosuppressive cytokines, such as interleukin-6 or VEGF, will be provided. mAbs which release co-inhibitory T cell receptors such as CTLA-4 and PD-1, overexpressed in HNSCC, also hold therapeutic promise. Finally, we will describe principles for therapeutic vaccination in HPV-associated HNSCC, where non-host TAs such as viral oncoproteins represent ideal targets, and HPV-negative HNSCC, where p53 is a promising target. Insights into immunosuppression in HNSCC have elucidated mechanistic targets for immunotherapy. Rational clinical investigation may lead to effective stand alone or combinatorial treatment approaches.
Insights
Head and neck squamous cell carcinoma (HNSCC) exhibits immunosuppression, hindering standard treatments. Novel immunotherapies targeting immune evasion mechanisms offer promising new treatment strategies for HNSCC patients.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Head and neck squamous cell carcinoma (HNSCC) is associated with poor survival and significant treatment-related side effects.
- The tumor microenvironment in HNSCC is characterized by a profoundly immunosuppressive profile, regardless of the cause (carcinogen exposure or human papillomavirus [HPV]).
- Previous immunotherapy trials faced challenges with systemic toxicity and local administration difficulties.
Purpose of the Study:
- To review the mechanisms of immune evasion employed by HNSCC.
- To discuss emerging immunotherapeutic strategies designed to overcome HNSCC-induced immunosuppression.
- To highlight potential targets for novel HNSCC treatments.
Main Methods:
- Summary of HNSCC immune escape mechanisms: reduced tumor antigen presentation, aberrant Signal Transducer and Activator of Transcription (STAT) pathway regulation, immunosuppressive cytokine production, and immune effector cell dysfunction.
- Review of therapeutic strategies including monoclonal antibodies (mAbs) targeting tumor antigens (e.g., cetuximab) and antibody-dependent cell-mediated cytotoxicity enhancement.
- Discussion of immunomodulation to rebalance STAT1/STAT3 activation, mAbs blocking immunosuppressive cytokines (e.g., IL-6, VEGF), and mAbs targeting co-inhibitory T cell receptors (e.g., CTLA-4, PD-1).
- Principles of therapeutic vaccination for HPV-associated HNSCC (targeting viral oncoproteins) and HPV-negative HNSCC (targeting p53).
Main Results:
- HNSCC utilizes multiple strategies to evade immune surveillance, including antigen presentation defects, STAT pathway dysregulation, and a suppressive cytokine milieu.
- Monoclonal antibodies targeting tumor antigens, enhancing immune cell activity, blocking immunosuppressive cytokines, and inhibiting co-inhibitory receptors show therapeutic potential.
- Therapeutic vaccination strategies are being developed for both HPV-associated and HPV-negative HNSCC, utilizing viral oncoproteins and p53 as targets, respectively.
Conclusions:
- Understanding HNSCC immunosuppression reveals critical targets for effective immunotherapy.
- Rational clinical trials investigating novel immunotherapies, alone or in combination, hold promise for improving outcomes in HNSCC patients.
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