CD8+CD103+ tissue-resident memory T cells convey reduced protective immunity in cutaneous squamous cell carcinoma

Abstract

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.

Presence of Skin Tissue-Resident Memory T Cells in Human Nonmalignant and Premalignant Melanocytic Skin Lesions and in Melanoma

“…3B). Consistent with data on healthy skin, 23,24 approximately 10% of CD3 + cells were CD103 + in human nevi (Fig. 3B).…”

Integrin αE(CD103)β7 in Epithelial Cancer

“…However, based on clinical and histological correlation studies [ 15 , 63 , 80 , 86 ], it is reasonable to assume that in some tumors CD103-expressing TILs enhance antitumor immune responses even in the absence of E-cadherin expression. However, that this is not true for all tumors is suggested by our observations and a recent study [ 79 ] in cutaneous squamous cell carcinoma.…”

“…These cells expressed more IL-10, PD-1 and CTLA-4 compared to CD103-negative cells. Moreover, the number of CD8 + CD103 + cells seemed to correlate with a rather unfavorable clinical course, which seems to contrast quite strikingly with findings in solid tumors of several other organs [ 79 ]. However, CD103 distribution in other epithelial skin tumors such as basal cell carcinomas or benign neoplasms is unknown.…”

Integrated analysis to reveal potential therapeutic targets and prognostic biomarkers of skin cutaneous melanoma

“…PTPRC is used as a prognostic indicator of cervical cancer ( 56 ), but its specific role in SKCM is still unclear. CD69 is significantly related to the tumor immune microenvironment and participates in the tumor immune infiltration process in melanoma ( 57 ). OIP5-AS1 protects microglia from hypoxia/ischemia-induced neuronal damage by sponging miR-186-5p ( 58 ).…”