Myeloid Dendritic Cells from Human Cutaneous Squamous Cell Carcinoma Are Poor Stimulators of T-Cell Proliferation

Abstract

In order to determine the phenotype and function of myeloid DCs from human cutaneous squamous cell carcinoma (SCC), we studied their surface marker expression and allo-stimulatory potential ex vivo. There were abundant CD11c+ myeloid DCs, as well as TNF and inducible nitric oxide synthase (iNOS)-producing DCs (TIP-DCs), in and around SCC tumor nests. Although myeloid DCs from SCC, adjacent non-tumor bearing skin, and normal skin, were phenotypically similar by flow cytometry, and there was a pronounced genomic signature of mature DCs in SCC, they showed different T cell stimulatory potential in an allo-MLR. Myeloid DCs from SCC were less potent stimulators of allogeneic T cell proliferation than DCs from non-tumor bearing skin. Culture with a DC-maturing cytokine cocktail (IL-1β, IL-6, TNF, and PGE2) enhanced stimulatory potential in DCs from non-tumor-bearing skin, while SCC associated DCs remained poor stimulators of T cell proliferation. The microenvironment associated with SCC showed expression of TGFβ, IL-10 and VEGF-A, factors capable of suppressing DC function. These findings indicate that CD11c+/HLA-DRhi DCs from SCC are mature, but are not potent stimulators of T cell proliferation compared with phenotypically similar DCs isolated from non-tumor-bearing skin. Identification of mechanisms responsible for suppression of tumor-associated DCs may provide insight into evasion of immunosurveillance by SCC.

Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22

“…CSA has also been associated with the promotion of fibroblast proliferation (15). Past studies in SCID mice have supported a role of TGF-β in immune evasion by SCC; our early work supports a role for TGF-β in SCC development (26,27). The current study sheds light on potential mechanisms for CSA-induced SCC in transplant patients utilizing tissue from catastrophic patients in our cohort.…”

Lung Cancer-Derived Galectin-1 Mediates Dendritic Cell Anergy through Inhibitor of DNA Binding 3/IL-10 Signaling Pathway

“…Accumulated evidence has also suggested that the emergence of tolerogenic DCs may be responsible for the development of tumor-mediated immune anergy (3,4). DCs isolated from animals and human cancer patients have phenotypic aberrations and functional loss (3,4). In addition, DCs located in the tumor's microenvironment not only inhibit T cell-based anticancer immune response, but promote the tumor's growth, and invasive and proangiogenic abilities (5)(6)(7).…”

“…Dendritic cells (DCs) play pivotal roles in initiating innate and adaptive immune responses, which are responsible for the induction of anticancer immune responses (2). Accumulated evidence has also suggested that the emergence of tolerogenic DCs may be responsible for the development of tumor-mediated immune anergy (3,4). DCs isolated from animals and human cancer patients have phenotypic aberrations and functional loss (3,4).…”

The chemokine microenvironment of Squamous Cell Carcinoma and its precursor lesions

“…This effect appears to rely upon proximity to the tumour core in cSCC, DCs from peritumoral skin were stronger stimulators of T-Cell proliferation compared to those more centrally located 21 The effective response of immune cell infiltration is reduced in invasive cSCC, and they are capable of evading the effective immune response through multiple mechanisms 22 .…”

“…Infiltration score (n = 0 (7), 1 (21), 2 (19), 3 (20) Infiltration score correlates strongly with chemokine expression One-Way ANOVA of increasing infiltration scoring correlated with the expression of IL-8…”