Increased Tc22 and Treg/CD8 Ratio Contribute to Aggressive Growth of Transplant Associated Squamous Cell Carcinoma

Abstract

Immune suppressed organ transplant recipients suffer increased morbidity and mortality from primary cutaneous SCC. We studied tumor microenvironment in transplant-associated SCC (TSCC), immune-competent SCC and normal skin by IHC, IF and RT-PCR on surgical discard. We determined T cell polarization in TSCC and SCC by intracellular cytokine staining of T cell crawl outs from human skin explants. We studied the effects of IL-22, an inducer of keratinocyte proliferation, on SCC proliferation in vitro. SCC and TSCC are both associated with significantly higher numbers of CD3⁺ and CD8⁺ T cells compared to normal skin. TSCC showed a higher proportion of Foxp3⁺ T regs to CD8⁺ T cells compared to SCC and a lower percentage of IFN-γ producing CD4⁺ T cells. TSCC, however, had a higher percentage of IL-22 producing CD8⁺ T cells compared to SCC. TSCC showed more diffuse Ki67 and IL-22 receptor (IL-22R) expression by IHC. IL-22 induced SCC proliferation in vitro despite serum starvation. Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression. Increased IL-22 and IL-22R expression could accelerate tumor growth in transplant patients. IL-22 may be an attractive candidate for targeted therapy of SCC without endangering allograft survival.