Administration of a vaccine composed of dendritic cells pulsed with premalignant oral lesion lysate to mice bearing carcinogen-induced premalignant oral lesions stimulates a protective immune response

Abstract

The use of dendritic cell (DC) vaccines as treatment for malignancy is complicated by immune evasion tactics often employed by carcinomas such as head and neck squamous cell carcinoma (HNSCC). The present study aims to determine if an immune response can be elicited by administering a DC vaccine during the premalignant stages of HNSCC, prior to development of immune escape. Mice treated with the carcinogen 4-nitroquinoline 1-oxide (4NQO) in drinking water develop premalignant oral lesions that progress to HNSCC. As previous studies demonstrated that premalignant lesions and HNSCC overexpress common tumor antigens, bone marrow-derived DCs were pulsed with premalignant lesion lysate (DCpm) and administered to 4NQO-treated mice exhibiting premalignant lesions. Lesion progression was tracked through endoscopy, which revealed that DCpm vaccination and control vaccination with dendritic cells pulsed with normal tongue epithelium lysate (DCnt) significantly decreased lesion burden at 8 weeks. Analysis of lymph node cells revealed that while DCnt vaccination resulted in a rapid increase in total lymphocyte count, levels of activated conventional CD4+ T cells and Th1, Tc1, Th17, Tc17, and Th2 cells, DCpm vaccination results in a delayed, yet substantial, increase in these immune effector mechanisms. This suggests that dendritic cell vaccination may have a beneficial effect on clinical outcome regardless of type of antigenic stimulation. Also, pulsing DCs with premalignant lysate rather than normal tongue epithelium lysate affects the dendritic cells in a way that delays the immune effector response upon vaccination of premalignant lesion-bearing mice.

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

“…To induce premalignant oral lesions that progress to oral cancer, female C57BL/6 mice (Charles Rivers Laboratory, Wilmington, MA) were treated with 50 μg/mL 4‐nitroquinoline 1‐oxide (4NQO) in their drinking water starting at 2 month of age 38, 39. After approximately 8 weeks of 4NQO treatment, mice developed endoscopically visible premalignant lesions on the tongue.…”

Treatment to sustain a Th17‐type phenotype to prevent skewing toward Treg and to limit premalignant lesion progression to cancer

“…A 5 mg/ml 4NQO stock solution in propylene glycol was diluted to 50 μg/ml and administered in the drinking water of 2 month old female C57BL/6 mice (Charles Rivers Laboratory, Wilmington, MA) . In this model, premalignant oral lesions appear after approximately 6 weeks of 4NQO treatment and HNSCC is detectable 10 weeks later after approximately 16 weeks of 4NQO treatment.…”

“…The failure of current therapies to prevent progression and the poor outcome for HNSCC patients supports the need for improved treatments. One model that has been developed for understanding premalignant oral lesions and their progression to cancer is a 4‐nitroquinoline‐1‐oxide (4NQO) carcinogen‐induced mouse model . The 4NQO carcinogen mimics the effects of tobacco products and induces premalignant oral lesions that are predominantly located on the tongue and which progress to oral cancer.…”

Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer

“…Using the photographic images, the total number and gross pathologic score of tongue lesions in 4-NQO-treated mice receiving either indomethacin or diluent control were blindly assessed, as previously described (24, 30). Lesions were scored on a 1–4 scale, with 1 indicating a flat macule, 2 indicating a raised papule, 3 indicating a raised plaque, and 4 indicating a grossly exophytic lesion.…”