Advances in Targeting Cutaneous Melanoma.

To date, the skin remains the most common cancer site among Caucasians in the western world. The complex, layered structure of human skin harbors a heterogenous population of specialized cells. Each cell type residing in the skin potentially gives rise to a variety of cancers, including non-melanoma skin cancer, sarcoma, and cutaneous melanoma. Cutaneous melanoma is known to exacerbate and metastasize if not detected at an early stage, with mutant melanomas tending to acquire treatment resistance over time. The intricacy of melanoma thus necessitates diverse and patient-centered targeted treatment options. In addition to classical treatment through surgical intervention and radio- or chemotherapy, several systemic and intratumoral immunomodulators, pharmacological agents (e.g., targeted therapies), and oncolytic viruses are trialed or have been recently approved. Moreover, utilizing combinations of immune checkpoint blockade with targeted, oncolytic, or anti-angiogenic approaches for patients with advanced disease progression are promising approaches currently under pre-clinical and clinical investigation. In this review, we summarize the current 'state-of-the-art' as well as discuss emerging agents and regimens in cutaneous melanoma treatment.

Characterization of KIR + NKG2A + Eomes- NK-like CD8+ T cells and their decline with age in healthy individuals.

BACKGROUND: KIR+NKG2A + Eomes+ CD8+ T cells, which are preferentially found with a TEMRA (CD45RA + CCR7-) phenotype while having the capacity to rapidly produce IFN-γ in response to innate stimulation (IL-12 and IL-18), have been demonstrated to exist in human cord blood and the adult blood circulation. This highly responsive T-cell type was termed NK-like CD8+ T cells due to their capability to act in an innate immune fashion in mice similar to NK cells. However, KIR+NKG2A + CD8+ T cells that are Eomes- represent a small proportion of unconventional T cells that have not been described until now. METHODS: We compare the distribution of the memory phenotypes and senescence-associated markers of two T-cell subsets by multicolor flow cytometry in 10 cord blood samples and 105 healthy individuals (HIs) ranging from 6 to 84 years of age. RESULTS: We found that the Eomes+ population has a higher differentiation degree than the Eomes- population. T cells in the Eomes- subset show proportionally less TEMRA phenotypes while instead preferentially displaying a more naïve and TCM phenotype. Furthermore, the Eomes- population was shown to linearly decrease with age, while the Eomes+ population exhibited more senescence-associated characteristics, such as CD57 expression and loss of CD28. CONCLUSION: Overall, the KIR+NKG2A + Eomes- CD8+ T-cell population shares similar characteristics with the Eomes+ population, although with a lower degree of differentiation, lower senescence marker expression, and a proportional decrease with age. Thus, we suspect that KIR+NKG2A + Eomes-CD8+ T cells may represent a less differentiated stage of the NK-like CD8+ T-cell subset.

Patched 1 expression in Merkel cell carcinoma.

The relevance of Hedgehog signaling in Merkel cell carcinoma has only been addressed by a few studies with conflicting results. Thus, we aimed to establish the expression of Hedgehog signaling molecules in Merkel cell carcinoma to characterize causes of aberrant expression and to correlate these findings with the clinical course of the patients. Immunohistochemistry was performed for Sonic, Indian, Patched 1 (PTCH1) and Smoothened on patients' tumor tissue. Respective mRNA expression was analyzed in 10 Merkel cell carcinoma cell lines using quantitative real-time polymerase chain reaction. PTCH1 sequencing and DNA methylation microarray analyses were carried out on tumor tissues as well as cell lines. PTCH1 immunoreactivity in Merkel cell carcinoma was similar to that of basal cell carcinomas, which both significantly differed from PTCH1 immunoreactivity in healthy skin. Most PTCH1 mutations found were synonymous or without known functional impact. However, on average, the promoter regions of both PTCH1 were hypomethylated independently from PTCH1 gene expression or Merkel cell polyomavirus status. PTCH1 and GLI1/2/3 genes were differently expressed in different cell lines; notably, there was a significant correlation between GLI2 and PTCH1 mRNA expression. Similar to PTCH1 protein expression in patient tissues, PTCH1 gene expression in Merkel cell carcinoma cell lines is highly variable, but due to the similar methylation pattern across Merkel cell carcinoma cell lines, effects other than methylation seem to be the reason for the differential expression and PTCH1 appears to be upregulated by GLI as a classical Hedgehog target gene.

Age related human T cell subset evolution and senescence.

T cells are fundamental effector cells against viruses and cancers that can be divided into different subsets based on their long-term immune protection and immediate immune response effects. The percentage and absolute number of these subsets change with ageing, which leads to a reduced immune response in older individuals. Stem cell memory T cells (TSCM) represent a small population of memory T cells with enhanced proliferation and differentiation properties that are endowed with high potential for maintaining T cell homeostasis. However, whether these cells change with ageing and gender remains unknown. Here, we assayed the distribution of TSCM and other T cell subsets in peripheral blood from 92 healthy subjects (44 females and 48 males) ranging from 3 to 88 years old by flow cytometry. We found that CD4+ and CD8+ TSCM in the circulation have relatively stable frequencies, and the absolute number of CD8+ TSCM decreased with age; however, the ratio of TSCM to the CD4+ or CD8+ naïve population increased with age. Unlike the obvious changes in other T cell subsets with age and gender, the stable level of TSCM in peripheral blood may support their capacity for sustaining long-term immunological memory, while their importance may increase together with ageing.

T cell senescence and CAR-T cell exhaustion in hematological malignancies.

T cell senescence has been recognized to play an immunosuppressive role in the aging population and cancer patients. Strategies dedicated to preventing or reversing replicative and premature T cell senescence are required to increase the lifespan of human beings and to reduce the morbidity from cancer. In addition, overcoming the T cell terminal differentiation or senescence from lymphoma and leukemia patients is a promising approach to enhance the effectiveness of adoptive cellular immunotherapy (ACT). Chimeric antigen receptor T (CAR-T) cell and T cell receptor-engineered T (TCR-T) cell therapy highly rely on functionally active T cells. However, the mechanisms which drive T cell senescence remain unclear and controversial. In this review, we describe recent progress for restoration of T cell homeostasis from age-related senescence as well as recovery of T cell activation in hematological malignancies.