Langerhans Cells from Human Cutaneous Squamous Cell Carcinoma Induce Strong Type 1 Immunity

Abstract

Purpose Langerhans cells [LCs] are dendritic cells [DCs] localized to the epidermis. They should be the first antigen presenting cells to encounter squamous cell carcinoma (SCC). The aim of this study was to investigate the ability of LCs isolated from human SCC to induce T cell proliferation and polarization. Experimental design We investigated the ability of LCs from SCC and peritumoral skin to induce T-cell proliferation and polarization. We also studied the effect of SCC supernatant on the ability of LCs from normal skin, in vitro generated LCs, and DCs to activate and polarize T cells. Results LCs from SCC were stronger inducers of allogeneic CD4+ and CD8+ T-cell proliferation and interferon (IFN)-γ production than LCs from peritumoral skin. We found that tumor supernatants were rich in immunosuppressive cytokines; despite this, allogeneic CD4+ and CD8+ T-cell proliferation and IFN-γ induction by LCs were augmented by tumor supernatant. Moreover, tumor supernatant facilitated IFN-γ induction by in vitro generated LCs, but suppressed the ability of in vitro generated DCs to expand allogeneic CD4+ and CD8+ T cells. Conclusions We have demonstrated that LCs from SCC can induce type-1 immunity. Tumor supernatant induces IFN-γ induction by in vitro generated LCs. This contrasts greatly with prior studies showing that DCs from SCC cannot stimulate T cells. These data indicate that LCs may be superior to DCs for SCC immunotherapy and may provide a novel rationale to harnessing LCs for the treatment of cancer patients.

An Animal Explant Model for the Study of Human Cutaneous Squamous Cell Carcinoma

“…We have previously shown that human SCC explants contain populations of myeloid dendritic cells [18], macrophages [17], Langerhans' cells [18], [31] and effector T cells including Th1, Th2, Th17, Th22 and Tc22 [31]. Tumor nests in the present model survive largely without resident inflammatory cells.…”

“…Our present data showing that LCs remain in SCC explants after 1 month might indicate a failure of migration, a failure of lymphatic vessel connection or both. We had previously shown that LCs from SCC are potent initiators of type 1 responses which might be beneficial to antitumor immunity [31]; despite this, SCC still occurs. Our findings may provide some preliminary evidence that the failure of Langerhans cells to stimulate an anti-tumor response in SCC, is not due a functional deficit, but rather that they are not migrating out of tumors to local nodes where they could present tumor antigen.…”

The molecular fingerprint of human papillomavirus infection and its effect on the Langerhans cell population in squamous cell carcinomas of the genital skin

“…They could also be inhibited by physical contact with regulatory T cells or by the presence of myeloid-derived suppressor cells in the tumor microenvironment. [35] LC might also be inactivated due to a lack of secretion of proinflammatory cytokines by the infected keratinocytes. It has been shown that HPV infection limits the capacity of the keratinocyte to secrete proinflammatory cytokines such as interferon α, interferon β, interleukin 1, interleukin 6, among others.…”

Interleukin-22 and Cyclosporine in Aggressive Cutaneous Squamous Cell Carcinoma

“…These cells are primarily found in tissues adjacent to and including the interface with the tumor. 24 Moreover, LCs from SCC have been shown to stimulate CD4+ and CD8+ T-cell proliferation at rates higher than those from normal skin eliciting a type 1 T-cell response. 24 In addition, they express higher levels of LC maturation markers, CD40, CD80, CD83, and CD86.…”

“…LCs from SCC have been reported to express immune-activating signal transducer and activator of transcription (STAT) 4, IL-15, and CD80, and immune tolerizing CD200 genes. 24 Therefore, it is possible that LCs can have protumor roles in the context of SCC, despite their ability to elicit T-cell responses.…”