Characterization of the evolution of immune phenotype during the development and progression of squamous cell carcinoma of the head and neck

Abstract

While studies have indicated that squamous cell carcinoma of the head and neck (HNSCC) is associated with immune suppression, these studies did not analyze the immune response at the dysplastic stage. The present study utilized a mouse model of 4-nitroquinoline 1-oxide-induced oral carcinogenesis to examine the alterations in immune phenotype at the premalignant and malignant stages of HNSCC. Cervical lymph nodes of HNSCC-bearing mice were found to contain a greater number of cells, including a greater number of conventional (Tconv) and regulatory (Treg) T cells, compared to cervical lymph nodes of control and premalignant lesion-bearing mice, though the Tconv cells appear to be less proliferative and the Treg cells appear to be less suppressive at the HNSCC stage. Premalignant lesion-bearing mouse lymph nodes consist of a greater percentage of Tconv cells expressing markers for activation, memory, and exhaustion compared to both control and HNSCC-bearing mice. Also, lymph nodes’ cells from both premalignant lesion-bearing and HNSCC-bearing mice include increased levels of Th1, Tc1, and Th17 cells, with no differences in levels of Th2 cells, compared to control mice. The data show that while there is the expected increase in immunosuppressive Tregs in lymph nodes when HNSCC is present, there is also an unexpected increase in immune populations usually associated with a beneficial antitumor response, including Tconv cells and Th1 and Tc1 cells. In addition, the results demonstrate that the premalignant stage of HNSCC development is associated with a robust immune response involving an increase in inflammatory Th1, Tc1, and Th17 cells.

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

“…This model represents the stages of carcinogenesis‐induced cancer described for tobacco products 41. In addition, similar to what has been shown for human subjects with premalignant lesions, we had previously shown that mice bearing 4NQO‐induced premalignant oral lesions have increased expression of PD‐1 on their CD4 + and CD8 + T‐cells 8. The results of this study showed an early increase in spleen cell secretion of the Th1 cytokine IL‐2 and the inflammatory cytokines IL‐6, IL‐17 and TNF‐α after one week of treatment with antibody against PD‐1, and an increase of IFN‐γ after 3 weeks of treatment.…”

“…The identity of these premalignant oral lesions and HNSCC was confirmed histologically. Clinical assessments of lesions were quantitated in a blinded manner by counting the number of visible lesions, and giving lesions a gross pathologic score between 1 and 4 based on their horizontal and vertical size, and overall appearance 8. The following criteria were used for scoring: 1: flat macule, 2: raised papule, 3: raised plaque, 4: grossly exophytic.…”

“…These high‐risk patients include those with thick leukoplakias on the floor of mouth, lip and tongue 6. Although vibrant immune reactivity is evident within premalignant oral lesions and adjacent lymph nodes, there is also evidence of immunological fatigue and a shift to immune inhibitory processes 7, 8, 9…”

T-helper and T-regulatory cells modulation in head and neck squamous cell carcinoma

“…Multiple studies have indicated that HNSCC is associated with immune suppression and this could explain the high reoccurrence rate of this type of cancer. 4 Malignant HNSCC cells may escape immune surveillance by different strategies: they can avoid immune recognition or they may affect immune system efficiency. For instance, recognition of tumor cell is hampered by the significant decrease of antigen-presenting cells and their effectiveness.…”

“…These data are sustained by studies in a murine model of 4-nitroquinoline-1-oxide induced oral carcinogenesis, where the progression from premalignant lesion to oral squamous cell carcinoma (OSCC) was characterized by a progressive increase of Th17 cells and IL-17. 4,31 How Th17 cells increase may be a favorable factor in tumor progression is still a matter of debate; nevertheless, one convincing hypothesis is that Th17 cells might have a significant role in promoting intra-tumor angiogenesis. 29 IL-17 steadily increases during HNSCC progression.…”