TY - JOUR T1 - Merkel cell polyomavirus-specific immune responses in patients with Merkel cell carcinoma receiving anti-PD-1 therapy JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-018-0450-7 VL - 6 IS - 1 SP - 131 AU - Natalie J. Miller AU - Candice D. Church AU - Steven P. Fling AU - Rima Kulikauskas AU - Nirasha Ramchurren AU - Michi M. Shinohara AU - Harriet M. Kluger AU - Shailender Bhatia AU - Lisa Lundgren AU - Martin A. Cheever AU - Suzanne L. Topalian AU - Paul Nghiem Y1 - 2018/12/01 UR - http://jitc.bmj.com/content/6/1/131.abstract N2 - Background Merkel cell carcinoma (MCC) is an aggressive skin cancer that frequently responds to anti-PD-1 therapy. MCC is associated with sun exposure and, in 80% of cases, Merkel cell polyomavirus (MCPyV). MCPyV-specific T and B cell responses provide a unique opportunity to study cancer-specific immunity throughout PD-1 blockade therapy.Methods Immune responses were assessed in patients (n = 26) with advanced MCC receiving pembrolizumab. Peripheral blood mononuclear cells (PBMC) were collected at baseline and throughout treatment. MCPyV-oncoprotein antibodies were quantified and T cells were assessed for MCPyV-specificity via tetramer staining and/or cytokine secretion. Pre-treatment tumor biopsies were analyzed for T cell receptor clonality.Results MCPyV oncoprotein antibodies were detectable in 15 of 17 (88%) of virus-positive MCC (VP-MCC) patients. Antibodies decreased in 10 of 11 (91%) patients with responding tumors. Virus-specific T cells decreased over time in patients who had a complete response, and increased in patients who had persistent disease. Tumors that were MCPyV(+) had a strikingly more clonal (less diverse) intratumoral TCR repertoire than virus-negative tumors (p = 0.0001).Conclusions Cancer-specific T and B cell responses generally track with disease burden during PD-1 blockade, in proportion to presence of antigen. Intratumoral TCR clonality was significantly greater in VP-MCC than VN-MCC tumors, suggesting expansion of a limited number of dominant clones in response to fewer immunogenic MCPyV antigens. In contrast, VN-MCC tumors had lower clonality, suggesting a diverse T cell response to numerous neoantigens. These findings reveal differences in tumor-specific immunity for VP-MCC and VN-MCC, both of which often respond to anti-PD-1 therapy.Natalie J. Miller and Candice D. Church contributed equally to this work.Abbreviations:CRComplete responseCTcomputed tomographyFFPEFormalin-fixed paraffin-embeddedHLA-IHuman leukocyte antigen class IIFN-γInterferon gammaIL-2Interleukin 2MCCMerkel cell carcinomaMCPyVMerkel cell polyomavirusPBMCPeripheral blood mononuclear cellsPDProgressive diseasePD-1Programmed cell death protein 1PD-L1Programmed death-ligand 1PRPartial responseRECISTResponse Evaluation Criteria in Solid TumorsSDStable diseaseSTUStandard Titer UnitsTCRT cell receptorUVUltravioletVN-MCCVirus-negative Merkel cell carcinomaVP-MCCVirus-positive Merkel cell carcinoma ER -