Understanding Dendritic Cells and Their Role in Cutaneous Carcinoma and Cancer Immunotherapy

Dendritic cells (DC) represent a diverse group of professional antigen-presenting cells that serve to link the innate and adaptive immune systems. Their capacity to initiate a robust and antigen-specific immune response has made them the ideal candidates for cancer immunotherapies. To date, the clinical impact of DC immunotherapy has been limited, which may, in part, be explained by the complex nature of DC biology. Multiple distinct subsets of DCs have been identified in the skin, where they can be broadly subcategorized into epidermal Langerhans cells (LC), myeloid-derived dermal dendritic cells (mDC) and plasmacytoid dendritic cells (pDC). Each subset is functionally unique and may activate alternate branches of the immune system. This may be relevant for the treatment of squamous cell carcinoma, where we have shown that the tumor microenvironment may preferentially suppress the activity of mDCs, while LCs remain potent stimulators of immunity. Here, we provide an in depth analysis of DC biology, with a particular focus on skin DCs and their role in cutaneous carcinoma. We further explore the current approaches to DC immunotherapy and provide evidence for the targeting of LCs as a promising new strategy in the treatment of skin cancer

Histopathological Variants of Cutaneous Squamous Cell Carcinoma: A Review

Nonmelanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population, with squamous cell carcinoma (SCC) accounting for the majority of NMSC-related metastases and death. While most SCC lesions are indolent tumors with low malignant potential, a wide diversity of SCC subtypes exist, several of which are associated with markedly more aggressive behaviors. Distinguishing these high-risk variants from their counterparts is possible through microscopic analysis, since each subtype possesses unique histopathological features. Early identification of high-risk lesions can allow for more rapid therapeutic intervention, reducing the likelihood of metastasis and death. The authors review specific histopathological features and associated clinical outcomes of the primary subdivisions of SCC

Histopathological Variants of Cutaneous Squamous Cell Carcinoma: A Review

Nonmelanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population, with squamous cell carcinoma (SCC) accounting for the majority of NMSC-related metastases and death. While most SCC lesions are indolent tumors with low malignant potential, a wide diversity of SCC subtypes exist, several of which are associated with markedly more aggressive behaviors. Distinguishing these high-risk variants from their counterparts is possible through microscopic analysis, since each subtype possesses unique histopathological features. Early identification of high-risk lesions can allow for more rapid therapeutic intervention, reducing the likelihood of metastasis and death. The authors review specific histopathological features and associated clinical outcomes of the primary subdivisions of SCC

Increased Tc22 and Treg/CD8 ratio contribute to aggressive growth of transplant associated squamous cell carcinoma.

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

The proposed model of accelerated development of TSCC.

<p>An increased proportion of T regs, combined with decreased numbers of CD8⁺ and IFN-γ producing T cells, leads to decreased tumor surveillance. Greater percentage of IL-22 producing T cells suggests an increased proliferation stimulus. The overall imbalance could explain the rapidly proliferative nature of TSCC. IL-22 blockade may be an attractive candidate for targeted SCC therapy, especially in the transplant population.</p

IL 22 increases the proliferation of human cutaneous SCC in vitro.

<p>A431 cells were cultured in full media (10% FBS) or in serum starvation media (0.1% FBS) with or without the addition of the indicated cytokines for 72 hours. (a) Cells cultured in full media, and in starvation media supplemented with IL-22 (40 ng/ml and 100 ng/ml) show considerably greater proliferative behavior with increased colony formation when compared to those grown in starvation media alone or supplemented with IL-24 (40 ng/ml). (b) Representative images of IF staining using the proliferation marker Ki-67 (green) and the nuclear stain DAPI (blue). Cells grown in full media, as well as those treated with IL-22 (40 ng/ml and 100 ng/ml) show an increased number of proliferating nuclei when compared to those grown in starvation media alone or supplemented with IL-24 (40 ng/ml). Additionally, they demonstrate a more disorganized pattern of proliferation, with KI67+ cells no longer limited to the periphery, but rather seen throughout the tumor colonies. (c) Cell counts were performed after 72 hours of cultivation in the indicated conditions. The addition of 100 ng/ml IL-22 to the starvation media (0.1% FBS) resulted in a hyperproliferation of tumor cells, yielding significantly greater cell numbers when compared to those grown in serum starvation alone, or serum starvation supplemented with IL-22 (40 ng/ml) or IL-24 (40 ng/ml) (one-way ANOVA, p<0.001).</p

IL-22 expression is increased in SCC, TSCC, and juxtatumoral skin.

<p>The relative mRNA expression of IL-22 relative to <i>Human Acidic Ribosomal Protein (HARP)</i> in normal (n = 9), SCC (n = 9), SCC peritumoral (n = 9), TSCC (n = 7), and TSCC peritumoral tissue (n = 7). Data expressed as mean relative mRNA expression ± standard error. Asterisks (*) indicate statistical significance, where <i>*P<0.05</i>.</p