Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA

被引：223

作者：

Paulson, K. G. ^{[1
,2
,3
]}

Voillet, V. ^{[2
]}

McAfee, M. S. ^{[2
]}

Hunter, D. S. ^{[2
]}

Wagener, F. D. ^{[2
]}

Perdicchio, M. ^{[2
,6
]}

Valente, W. J. ^{[2
]}

Koelle, S. J. ^{[1
,2
]}

Church, C. D. ^{[1
]}

Vandeven, N. ^{[1
]}

Thomas, H. ^{[1
]}

Colunga, A. G. ^{[1
]}

Iyer, J. G. ^{[1
]}

Yee, C. ^{[4
]}

Kulikauskas, R. ^{[1
]}

Koelle, D. M. ^{[1
,2
,5
]}

Pierce, R. H. ^{[2
]}

Bielas, J. H. ^{[1
,2
]}

Greenberg, P. D. ^{[1
,2
]}

Bhatia, S. ^{[1
,2
,3
]}

Gottardo, R. ^{[1
,2
]}

Nghiem, P. ^{[1
,2
,3
]}

Chapuis, A. G. ^{[1
,2
,3
]}

机构：

[1] Univ Washington, Seattle, WA 98195 USA

[2] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA

[3] Seattle Canc Care Alliance, Seattle, WA 98109 USA

[4] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[5] Benaroya Res Inst, Seattle, WA USA

[6] Roche, Basel, Switzerland

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

MERKEL CELL-CARCINOMA; T-CELLS; DOWN-REGULATION; PD-1; BLOCKADE; POLYOMAVIRUS; EXPRESSION; PEMBROLIZUMAB; IPILIMUMAB; REGRESSION; MUTATIONS;

D O I：

10.1038/s41467-018-06300-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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