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

Abstract

A carcinogen‐induced premalignant oral lesion model that progresses to oral cancer was used to examine the impact of blocking PD‐1 on cytokine expression and on progression of lesions to cancer. The results of this study show increased production of IL‐2 and the inflammatory cytokines IL‐6, IL‐17 and TNF‐α by spleen cells of lesion‐bearing mice that were treated with PD‐1 antibody for 1 week compared to cytokine production by spleen cells of lesion‐bearing mice treated with control antibody. Production of IFN‐γ increased at 3 weeks of PD‐1 antibody treatment, although production of the other Th1 and inflammatory mediators declined. By 5 weeks, levels of these cytokines declined for both control and PD‐1 antibody‐treated mice. Flow cytometric analysis for IFN‐γ‐expressing cells showed shifts in CD4+ cells expressing IFN‐γ consistent with the changes in cytokine secretion. Whether or not treatment generated reactivity to lesions or HNSCC was determined. Spleen cells from PD‐1 antibody‐treated mice were stimulated by lysates of premalignant lesion and HNSCC tongue tissues to produce increased levels of Th1 and select inflammatory cytokines early in the course of PD‐1 antibody treatment. However, with continued treatment, reactivity to lesion and HNSCC lysates declined. Analysis of clinical response to treatment suggested an early delay in lesion progression but, with continued treatment, lesions in PD‐1 antibody‐treated mice progressed to the same degree as in control antibody‐treated mice. Overall, these results show an early beneficial response to PD‐1 antibody treatment, which then fails with continued treatment and lesion progression.

Local Immune Responsiveness of Mice Bearing Premalignant Oral Lesions to PD-1 Antibody Treatment

“…The present study also confirmed our prior results demonstrating that PD-1 treatment caused an early, but transient, increase in spleen cell production of Th1 and inflammatory cytokines which was seen after 1 week of PD-1 antibody treatment and declined thereafter [29]. The exception was IFN-γ, which peaked after 3 weeks of treatment before declining.…”

“…These results for IFN-γ contrasted with results for lymph node secretion of the inflammatory mediators IL-17 or TNF-α in response to a lesion or cancer challenge, which was greater for control antibody-treated mice. The responses of lymph node cells to lesion or HNSCC lysate challenges were transient, which is consistent with what we previously demonstrated for spleen cell responses to challenge [29]. It is also consistent with the transient increase in levels of cytokines within tongue tissue of PD-1 antibody-treated mice and with the transient increase in spontaneous spleen cell secretion of cytokines.…”

“…Our prior study showed a transient delay in the progression of premalignant oral lesions toward cancer in mice that were treated with PD-1 antibody, but then a pronounce advancement toward cancer [29]. This clinical response was confirmed in the present study by endoscopic examination of the oral cavity (Figure 7).…”

Tumor necrosis factor alpha secreted from oral squamous cell carcinoma contributes to cancer pain and associated inflammation

“…GM-CSF has shown to be increased in T lymphocytes after nerve injury [17] and when injected directly into the skin results in nociceptive behavior [61]. However, because TNFα was identified as a primary mediator upregulated with anti-PD-1/PD-L1 therapy [13,41], we will focus on TNFα for subsequent experiments.…”

“…This therapeutic tactic has shown promise for oral cancers [9,41,79]. Inhibition of the PD-1/PD-L1 pathway using monoclonal antibodies enhances leukocyte infiltration and increases tumor necrosis factor alpha (TNFα) secretion into the oral cancer microenvironment [42].…”