Tet+ = tetramer-positive. lymphocyte infiltration. Conclusions MCC-targeting T cells expand with tumor burden and express high levels of immune checkpoint receptors PD-1 and Tim-3. Reversal of these inhibitory pathways is therefore a promising therapeutic approach for this virus-driven cancer. Introduction Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a disease-associated mortality three times that of malignant melanoma (~46% versus 15%, respectively) (1). MCC is increasingly common with an estimated 1,600 cases/year in the US (2), and the reported incidence has more than tripled over the past 20 years (3). This increasing incidence is partly due to improved detection using a specific immunohistochemical marker, cytokeratin-20 (4), but may also be due to the higher prevalence of known risk factors for MCC: chronic T-cell WAY-262611 immune suppression and the number of Caucasians over 50 years of age with extensive prior sun exposure (5). Furthermore, the recent discovery of the Merkel cell polyomavirus (MCPyV) and its causal association with at least 80% of MCCs(6C8) has provided insight into MCC pathogenesis and underscores the importance of characterizing MCPyV-specific immune responses. The necessary and persistent (7)expression of MCPyV T-antigen (T-Ag) oncoproteins in MCC tumors provides an opportunity to study anti-tumor immunity by assessing responses against a viral, tumor-specific antigen. Although the role of T cells is variable among different human cancers, multiple lines of evidence suggest that cellular immune function is unusually important for survival in MCC. We have previously demonstrated that intratumoral CD8 lymphocyte infiltration (9)and lack of systemic immune suppression (10) are each significantly associated with improved survival. Furthermore, recent evidence suggests that MCC patients have T cells that are specific for persistently expressed viral oncoproteins(11). In this study, we made use of an extensive collection of clinically annotated longitudinally collected blood specimens to track the frequency and function of MCPyV-specific CD8 T cells. It is hoped that characterizing the molecular pathways involved in the inhibition of MCPyV-specific T cell responses may guide the design of rational therapies WAY-262611 to overcome tumor immune escape. To assess the functional state of MCC-targeting CD8 T cells, it was critical to determine the expression of physiologically relevant cell surface markers directly from tumors or blood. Key pathways examined included those associated with T cell inhibition (programmed death 1, PD-1; T cell immunoglobulin and mucin-domain, Tim-3; cytotoxic T-lymphocyte antigen 4, CTLA-4), co-stimulation and activation (CD28, CD69, CD137). Many WAY-262611 of these molecules are the targets of therapeutic agents Rabbit polyclonal to HOMER1 that are FDA approved (ipilimumab for CTLA-4)or are in clinical (PD-1, CD137 or 4-1BB) (12, 13)or pre-clinical (Tim-3)(14, 15) trials. We show that while MCPyV-specific T cell frequency increases and decreases in parallel with disease burden, these cells display an exhausted phenotypic profile throughout the disease course. Importantly, this study identifies key inhibitory and activation pathways that may be suitable therapeutic targets for reversing T cell dysfunction and promoting anti-tumor responses. Materials and Methods Human subjects and samples This study was approved by the Fred Hutchinson Research Center WAY-262611 IRB and conducted according to Declaration of Helsinki principles. Informed consent was received from WAY-262611 all participants. Blood was obtained from HLA-A*2402+, HLA-A*2301+ or HLA-A*0201+ subjects based on HLA restriction of available tetramers. Tumors were obtained from medically necessary procedures. Tumor MCPyV status was assessed by RT-PCR for MCPyV T-Ag, immunohistochemistry (CM2B4 antibody, Santa Cruz) and/or T-Ag serology (9). Extent of disease was determined by clinical evaluation and staging by AJCC 7th edition guidelines. T-cell.
Posted by By stemcellresearchformichigan September 27, 2021
Overexpression of HNF1A-AS1 enhanced cell proliferation and promoted cell routine development, whereas knockdown of HNF1A-AS1 elicited the contrary effects