The immune system plays a key role in the development, establishment, and progression of head and neck squamous cell carcinoma (HNSCC). A greater understanding of the dysregulation and evasion of the ...immune system in the evolution and progression of HNSCC provides the basis for improved therapies and outcomes for patients. HNSCC cells evade the host immune system through manipulation of their own immunogenicity, production of immunosuppressive mediators, and promotion of immunomodulatory cell types. Through the tumor's influence on the microenvironment, the immune system can be exploited to promote metastasis, angiogenesis, and growth. This article provides a brief overview of key components of the immune infiltrating cells in the tumor microenvironment, reviewing immunological principles related to head and neck cancer, including the concept of cancer immunosurveillance and immune escape. Current immunotherapeutic strategies and emerging results from ongoing clinical trials are presented.
Head and neck cancers are a heterogeneous collection of malignancies of the upper aerodigestive tract, salivary glands and thyroid. In this Review, we primarily focus on the changing therapeutic ...landscape of head and neck squamous cell carcinomas (HNSCCs) that can arise in the oral cavity, oropharynx, hypopharynx and larynx. We highlight developments in surgical and non-surgical therapies (mainly involving the combination of radiotherapy and chemotherapy), outlining how these treatments are being used in the current era of widespread testing for the presence of human papillomavirus infection in patients with HNSCC. Finally, we describe the clinical trials that led to the approval of the first immunotherapeutic agents for HNSCC, and discuss the development of strategies to decrease the toxicity of different treatment modalities.
•Three randomized I trials have shown that PD-1 inhibitors prolong survival in R/M HNSCC.•In first-line R/M HNSCC pembrolizumab monotherapy is approved if PD-L1 positive. BULLET: Pembrolizumab is ...also approved in combination with chemotherapy in this setting.•85% of R/M HNSCC are PD-L1 positive (combined positive score ≥1).•Clinical judgment will guide selection of pembrolizumab monotherapy or plus chemotherapy.
Three randomized phase III trials have now conclusively proven that exposure to a PD-1 inhibitor prolongs survival in recurrent/metastatic (R/M) HNSCC, and it is clear that such agents should be used in the management of all patients who do not have contraindications to their use. Two of these phase III randomized trials showed that the anti-PD1 antibodies nivolumab and pembrolizumab were superior to investigators′ choice chemotherapy in second-line platinum-refractory R/M HNSCC. Recently, a third phase III randomized trial, KEYNOTE-048, showed that pembrolizumab with chemotherapy was superior to the EXTREME regimen (cis- or carboplatin, 5-fluorouracil (5-FU) and cetuximab) in all patients, and pembrolizumab monotherapy was superior in patients whose tumors express PD-L1 in first-line R/M HNSCC. Pembrolizumab is now approved as monotherapy in PD-L1 expressing disease (combined positive score ≥1) or in combination with chemotherapy for all patients with R/M HNSCC. Thus, PD-L1 biomarker testing will be routinely used in R/M HNSCC, and this employs a scoring system that incorporates immune cell staining, referred to as the combined positive score (CPS). Additionally, for the 85% of patients with PD-L1 CPS ≥1, clinical judgment will guide the choice of pembrolizumab monotherapy or pembrolizumab plus chemotherapy, until more detailed clinical data are forthcoming to better inform this decision. In this article we discuss the clinical trials leading to these therapeutic advances and we will review initial results from clinical trials in previously untreated, locally advanced disease, and those using novel combinations of checkpoint inhibitors, co-stimulatory agonists, and therapeutic vaccines.
Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Here, we assessed the transcriptional ...profiles of 131,224 single cells from peripheral and intra-tumoral immune populations from patients with HPV– and HPV+ HNSCC and healthy donors. Immune cells within tumors of HPV– and HPV+ HNSCC displayed a spectrum of transcriptional signatures, with helper CD4+ T cells and B cells being relatively divergent and CD8+ T cells and CD4+ regulatory T cells being relatively similar. Transcriptional results were contextualized through multispectral immunofluorescence analyses and evaluating putative cell-cell communication based on spatial proximity. These analyses defined a gene expression signature associated with CD4+ T follicular helper cells that is associated with longer progression-free survival in HNSCC patients. The datasets and analytical approaches herein provide a resource for the further study of the impact of immune cells on viral- and carcinogen-induced cancers.
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•Single-cell RNA-seq revealed distinct immune profiles in HPV– and HPV+ HNSCC•B cells, myeloid cells, and CD4+ Tconv cells were divergent by high-dimensional analysis•Multispectral imaging uncovered immune structures (TLSs) associated with HPV+ disease•T follicular helper signature was associated with favorable survival in TCGA patients
Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or human papillomavirus (HPV). Cillo et al. determine single-cell transcriptional profiles of peripheral and intra-tumoral immune populations from patients with HPV– and HPV+ HNSCC and healthy donors. These datasets, accompanied by spatial organization information, provide a resource for further study of immunity to viral- and carcinogen-induced cancers.
Transoral endoscopic head and neck surgery is a new approach for the treatment of oropharyngeal tumors. Using either a robotic system and/or laser, surgeons gain access through the mouth via ...minimally invasive technique and thus have improved visualization of the tumors of the oropharynx, without disfiguring incisions. This transoral route of access minimizes long-term speech and swallowing dysfunction. Surgeons view this approach as a considerable technologic advance, analogous to the evolution in radiation therapy from conventional two- and three-dimensional conformal techniques to intensity-modulated techniques. Although the use of radiation with or without chemotherapy to treat oropharyngeal cancer (OPC) is supported by evidence from prospective clinical trials, there are no prospective data supporting the use of this new surgical approach for OPC. Here, we review the fundamentals of transoral endoscopic head and neck surgery, with robotics and laser technology, and discuss ongoing clinical trials for patients with OPC.
Purpose of Review
Discussion of current strategies targeting the immune system related to solid tumors with emphasis on head and neck squamous cell carcinoma (HNSCC).This review will outline the ...current challenges with immunotherapy and future goals for treatment using these agents.
Recent Findings
Agents targeting immune checkpoint receptors (IR) such as program death 1 (PD1) have been used in the clinical realm for melanoma and non-small cell lung cancer (NSCLC), and the use of these agents for these malignancies has provided crucial information about how and why patients respond or not to inhibitory checkpoint receptor blockade therapy (ICR). The anti PD1 agent, nivolumab, was recently approved by the FDA as a standard of care regimen for patients with platinum refractory recurrent/metastatic (R/M) HNSCC. Molecular pathways leading to resistance are starting to be identified, and work is underway to understand the most optimal treatment regimen with incorporation of immunotherapy.
Summary
ICR has renewed interest in the immunology of cancer, but resistance is not uncommon, and thus understanding of these mechanisms will allow the clinician to appropriately select patients that will benefit from this therapy.
Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we ...studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC.
E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index.
Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented.
Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.
Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and ...programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this novel therapy. T cell immunoglobulin and mucin domain 3 (TIM-3) has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity. Thus, targeting TIM-3 emerges as a promising approach for further improvement of current immunotherapy. Despite a large amount of experimental data showing an immune suppressive function of TIM-3 in vivo, the exact mechanisms are not well understood. To enable effective targeting of TIM-3 for tumor immunotherapy, further in-depth mechanistic studies are warranted. These studies will also provide much-needed insight for the rational design of novel combination therapy with other checkpoint blockers. In this review, we summarize key evidence supporting an immune regulatory role of TIM-3 and discuss possible mechanisms of action.
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