Different molecular subtypes can be identified in muscle-invasive bladder cancer. Although cisplatin-based neoadjuvant chemotherapy improves patient outcomes, we identified that the benefit is highest in patients with basal tumors. Our newly discovered classifier can identify these molecular subtypes in a single patient and could be integrated into routine clinical practice after further validation.

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Summary Background Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers capable of metastasizing. Proteomic analysis of cSCCs can provide insight into the biological processes responsible for metastasis, as well as future therapeutic targets and prognostic biomarkers. Objectives To identify proteins associated with development of metastasis in cSCC. Methods A proteomic‐based approach was employed on 105 completely excised, primary cSCCs, comprising 52 that had metastasized (P‐M) and 53 that had not metastasized at 5 years post‐surgery (P‐NM). Formalin‐fixed, paraffin‐embedded cSCCs were microdissected and subjected to proteomic profiling after one‐dimensional (1D), and separately two‐dimensional (2D), liquid chromatography fractionation. Results A discovery set of 24 P‐Ms and 24 P‐NMs showed 144 significantly differentially expressed proteins, including 33 proteins identified via both 1D and 2D separation, between P‐Ms and P‐NMs. Several differentially expressed proteins were also associated with survival in SCCs of other organs. The findings were verified by multiple reaction monitoring on six peptides from two proteins, annexin A5 (ANXA5) and dolichyl‐diphosphooligosaccharide–protein glycosyltransferase noncatalytic subunit (DDOST), in the discovery group and validated on a separate cohort (n = 57). Increased expression of ANXA5 and DDOST was associated with reduced time to metastasis in cSCC and decreased survival in cervical and oropharyngeal cancer. A prediction model using ANXA5 and DDOST had an area under the curve of 0·93 (confidence interval 0·83–1·00), an accuracy of 91·2% and higher sensitivity and specificity than cSCC staging systems currently in clinical use. Conclusions This study highlights that increased expression of two proteins, ANXA5 and DDOST, is significantly associated with poorer clinical outcomes in cSCC.

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BackgroundTumor infiltrating lymphocytes play a key role in antitumor responses; however, while several memory T-cell subtypes have been reported in inflammatory and neoplastic conditions, the proportional representation of the different subsets of memory T cells and their functional significance in cancer is unclear. Keratinocyte skin cancer is one of the most common cancers globally, with cutaneous squamous cell cancer (cSCC) among the most frequent malignancies capable of metastasis.MethodsMemory T-cell subsets were delineated in human cSCCs and, for comparison, in non-lesional skin and blood using flow cytometry. Immunohistochemistry was conducted to quantify CD103+ cells in primary human cSCCs which had metastasized (P-M) and primary cSCCs which had not metastasized (P-NM). TIMER2.0 (timer.cistrome.org) was used to analyze TCGA cancer survival data based on ITGAE expression. Immunofluorescence microscopy was performed to determine frequencies of CD8+CD103+ cells in P-M and P-NM cSCCs.ResultsDespite intertumoral heterogeneity, most cSCC T cells were CCR7−/CD45RA− effector/resident memory (TRM) lymphocytes, with naive, CD45RA+/CCR7− effector memory re-expressing CD45RA, CCR7+/L-selectin+ central memory and CCR7+/L-selectin− migratory memory lymphocytes accounting for smaller T-cell subsets. The cSCC CD8+ T-cell population contained a higher proportion of CD69+/CD103+ TRMs than that in non-lesional skin and blood. These cSCC CD69+/CD103+ TRMs exhibited increased IL-10 production, and higher CD39, CTLA-4 and PD-1 expression compared with CD103− TRMs in the tumor. CD103+ cells were more frequent in P-M than P-NM cSCCs. Analysis of TCGA data demonstrated that high expression of ITGAE (encoding CD103) was associated with reduced survival in primary cutaneous melanoma, breast carcinoma, renal cell carcinoma, kidney chromophobe cancer, adrenocortical carcinoma and lower grade glioma. Immunofluorescence microscopy showed that the majority of CD103 was present on CD8+ T cells and that CD8+CD103+ cells were significantly more frequent in P-M than P-NM cSCCs.ConclusionThese results highlight CD8+CD103+ TRMs as an important functional T-cell subset associated with poorer clinical outcome in this cancer.