Comparative Immune Phenotypic Analysis of Cutaneous Squamous Cell Carcinoma and Intraepidermal Carcinoma in Immune-Competent Individuals: Proportional Representation of CD8+ T-Cells but Not FoxP3+ Regulatory T-Cells Is Associated with Disease Stage

Abstract

Squamous Cell Carcinoma (SCC) is a type of non-melanoma skin cancer prevalent in immune-suppressed transplant recipients and older individuals with a history of chronic sun-exposure. SCC itself is believed to be a late-stage manifestation that can develop from premalignant lesions including Intraepidermal Carcinoma (IEC). Notably, while SCC regression is rare, IEC typically regresses in response to immune modifying topical treatments, however the underlying immunological reasons for these differential responses remain unclear. This study aimed to define whether IEC and SCC are associated with distinct immune profiles. We investigated the immune cell infiltrate of photo-damaged skin, IEC, and SCC tissue using 10-colour flow cytometry following fresh lesion digest. We found that IEC lesions contain higher percentages of CD3+ T-cells than photo-damaged skin, however, the abundance of CD3−CD56+ Natural Killer (NK) cells, CD11c+HLA-DR+ conventional Dendritic Cells (cDC), BDCA-2+HLA-DR+ plasmacytoid DC (pDC), FoxP3+ Regulatory T-cells (T-reg), Vα24+Vβ11+ invariant NKT-cells, and γδ Tcells did not alter with disease stage. Within the total T-cell population, high percentages of CD4+ T-cells were associated with SCC, yet CD8+ T-cells were less abundant in SCC compared with IEC. Our study demonstrates that while IEC lesions contain a higher proportion of T-cells than SCC lesions in general, SCC lesions specifically display a lower abundance of CD8+ T-cells than IEC. We propose that differences in CD8+ T-cell abundance contribute critically to the different capacity of SCC and IEC to regress in response to immune modifying topical treatments. Our study also suggests that a high ratio of CD4+ T-cells to CD8+ T-cells may be a immunological diagnostic indicator of late-stage SCC development in immune-competent patients.

Altered density, composition and microanatomical distribution of infiltrating immune cells in cutaneous squamous cell carcinoma of organ transplant recipients

“…The characteristics of the OTR and immunocompetent groups, including clinical and histopathological parameters, are presented in Table . As chronic ultraviolet‐damage of the skin and histological grading of SCC has been reported to alter local immune responses, we took great care to match the two cohorts for age, tumour site and tumour grading. As the impact of different immunosuppressive regimens on the cutaneous microenvironment and skin carcinogenesis is a topic of ongoing debate and direct pro‐ and antioncogenic effects have been described for commonly used immunosuppressive agents, we included only renal transplant patients in our OTR group, all being treated at a single transplant centre.…”

The Distribution of CD8- and Foxp3-positive T Cells in Skin Squamous Cell Tumors and Basal Cell Carcinomas

“…Our study did not show any difference in the degree of immune evasion between BD and SCC. A recent study analyzing immune phenotype in the SCC and BD of immunocompetent patients reported that SCC showed less infiltration of CD8 positive T cells and higher CD4 positive T cell/CD8+ T cell ratio than BD [9]. This finding suggests that the level of immune evasion is higher in SCC than in BD and further study for CD4 positive T cell subpopulation is necessary.…”

Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research

“…61,62 Xenograft Models and Humanized Mice Xenograft models, which involve the transplantation of human cancer cell lines, or patient-derived tumor cells in the case of patient-derived xenograft models, into immunodeficient mice represent another commonly used mouse model for cancer research. [63][64][65] These models offer a unique tool for testing anticancer drugs targeting human proteins in mutated cancer as well as individualized and patient-specific treatments. 55 Moreover, engraftment of surgically resected tumor biopsies into these immunodeficient mice allows for an in vivo system, where interactions between, for instance, tumor cells and stromal cells can be evaluated.…”