@article{c468aa2b76cc4047a1a6d7dd39d74fd1,
title = "Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA",
abstract = "Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor–immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.",
author = "Paulson, {K. G.} and V. Voillet and McAfee, {M. S.} and Hunter, {D. S.} and Wagener, {F. D.} and M. Perdicchio and Valente, {W. J.} and Koelle, {S. J.} and Church, {C. D.} and N. Vandeven and H. Thomas and Colunga, {A. G.} and Iyer, {J. G.} and C. Yee and R. Kulikauskas and Koelle, {D. M.} and Pierce, {R. H.} and Bielas, {J. H.} and Greenberg, {P. D.} and S. Bhatia and R. Gottardo and P. Nghiem and Chapuis, {A. G.}",
note = "Funding Information: Competing Interests: A.G. Chapuis has received support from Juno therapeutics. P.D.G. has received support and has ownership interest in Juno Therapeutics, Immune Design, and Innate Pharma. P.N. has received consulting fees from EMD Serono, Pfizer, Merck Sharpe and Dohne, Amgen, Incyte, Takeda, Mallinckrodt and research support from EMD Serono and Bristol-Meyers Squibb. A.G.C., M.S.M., D.M.K., K.G.P., C.D.C., and P. N. and their institutions have intellectual property related to T cell receptors recognizing Merkel cell polyomavirus. S.B. has received advisory board honoraria from Genentech and EMD-Serono; his institution (University of Washington) has received research funding from EMD-Serono, Merck, BMS, Oncosec, and Immune Design. A.G. Chapuis and K.G.P. have received reagents from 10X genomics. R.G. received consulting fees from Juno Therapeutics. The authors declare no other competing interests. Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41467-018-06300-3",
language = "English (US)",
volume = "9",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}