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Our results showed that the immune neutralization of PD-1+ cells resulted in decreased papilloma incidence associated with CD4+ and CD8+ T cells infiltrate, higher levels of interferon-γ and decreased levels of transforming growth factor-β in the tumor lesions. These findings support the role of PD-1 blockade as a promising component of immunotherapy against SCC.Engagement of programmed death-1 (PD-1) with its two ligands [programmed death ligand-1 (PD-L1) and PD-L2] has been associated with the suppression of tumor-reactive T cells; however, the underlying mechanism for this T-cell dysfunction is not clear. We hypothesized that PD-1 and PD-L1 signals are, in part, responsible for squamous cell carcinoma (SCC) escape from immune antitumor regulation by modulation of the tumor environment. In the present study, we used a multistage model of SCC to examine the role of PD-1/PD-L1 activation during tumor development. Tumor sites presented an increased percentage of CD4+ and CD8+ T cells expressing PD-1 when compared with non-tumorigenic control mice, whereas the expression of PD-L1 was particularly increased in F4/80+ macrophages in tumor sites. Further, the systemic immune neutralization of PD-1 resulted in a decreased number and delayed incidence rate of papillomas followed by a differential expression of cytokeratins, suggesting that the PD-1–PD-L1 interaction contributes to the progression of SCC by downregulation of antitumor responses. In fact, blocking PD-1 increased the percentage of CD8+ and CD4+ T cells, and the levels of interferon-γ in the tumor sites. Our results indicated involvement of PD-1+ T cells in SCC development and in the modulation of the inflammatory immune response. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma (SCC) constitutes a microenvironment that could modulate the antitumor immune response. Also, tumor-infiltrating lymphocytes are believed to play complex regulatory roles in antitumor immunity against SCC. The presence of regulatory T cells (Tregs) has been associated with the suppression of tumor-reactive T cells. However, the underlying mechanism for this T cell dysfunction is not clear. We used a multistage model of SCC to examine the role of Treg cells during tumor development. 7,12-dimethylbenz[a]-anthracene/phorbol 12-myristate 13-acetate treatment and systemic depletion of Treg cells using an anti-CD25 monoclonal antibody (PC61) resulted in a decrease in the number and incidence of papilloma. Furthermore, CD25 depletion increased the proportion of CD8+ and CD4+ T cells that were isolated from tumor lesions. The levels of interleukin (IL)-1β, IL-10, IL-12, IL-13, interferon-γ, transforming growth factor-β and tumor necrosis factor-α, but not IL-17, were increased in the tumor microenvironment after Treg depletion. Therefore, our results indicated involvement of CD25+ T cells in SCC development and in the suppression of the inflammatory immune response. [ABSTRACT FROM AUTHOR]