Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

被引：174

作者：

Au, Lewis ^{[1
,2
]}

Hatipoglu, Emine ^{[2
,3
,4
]}

de Massy, Marc Robert ^{[3
,4
]}

Litchfield, Kevin ^{[5
]}

Beattie, Gordon ^{[3
,4
]}

Rowan, Andrew ^{[5
]}

Schnidrig, Desiree ^{[1
]}

Thompson, Rachael ^{[6
]}

Byrne, Fiona ^{[1
]}

Horswell, Stuart ^{[7
]}

Fotiadis, Nicos ^{[8
,9
]}

Hazell, Steve ^{[10
]}

Nicol, David ^{[11
]}

Shepherd, Scott T. C. ^{[1
,2
]}

Fendler, Annika ^{[1
]}

Mason, Robert ^{[2
]}

Del Rosario, Lyra ^{[2
]}

Edmonds, Kim ^{[2
]}

Lingard, Karla ^{[2
]}

Sarker, Sarah ^{[2
]}

Mangwende, Mary ^{[2
]}

Carlyle, Eleanor ^{[2
]}

Attig, Jan ^{[6
]}

Joshi, Kroopa ^{[3
,4
]}

Uddin, Imran ^{[3
,4
,20
]}

Becker, Pablo D. ^{[3
]}

Sunderland, Mariana Werner ^{[3
]}

Akarca, Ayse ^{[12
]}

Puccio, Ignazio ^{[12
]}

Yang, William W. ^{[12
]}

Lund, Tom ^{[13
]}

Dhillon, Kim ^{[12
]}

Vasquez, Marcos Duran ^{[3
,4
]}

Ghorani, Ehsan ^{[3
,4
]}

Xu, Hang ^{[5
]}

Spencer, Charlotte ^{[1
]}

Lopez, Jose, I ^{[14
]}

Green, Anna ^{[15
]}

Mahadeva, Ula ^{[15
]}

Borg, Elaine ^{[12
]}

Mitchison, Miriam ^{[12
]}

Moore, David A. ^{[4
,12
]}

Proctor, Ian ^{[12
]}

Falzon, Mary ^{[12
]}

Pickering, Lisa ^{[2
]}

Furness, Andrew J. S. ^{[2
]}

Reading, James L. ^{[3
,4
]}

Salgado, Roberto ^{[16
,17
]}

Marafioti, Teresa ^{[12
]}

Jamal-Hanjani, Mariam ^{[4
,18
,19
]}

机构：

[1] Francis Crick Inst, Canc Dynam Lab, London NW1 1AT, England

[2] Royal Marsden NHS Fdn Trust, Renal & Skin Unit, London SW3 6JJ, England

[3] UCL, Res Dept Hematol, Canc Immunol Unit, Canc Inst, London WC1E 6DD, England

[4] UCL, Canc Res UK Lung Canc Ctr Excellence, Canc Inst, London WC1E 6DD, England

[5] Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London NW1 1AT, England

[6] Francis Crick Inst, Retroviral Immunol, London NW1 1AT, England

[7] Francis Crick Inst, Dept Bioinformat & Biostat, London NW1 1AT, England

[8] Inst Canc Res, Canc Res UK Canc Imaging Ctr, Div Radiotherapy & Imaging, London SW3 6JJ, England

[9] Royal Marsden Hosp, London SW3 6JJ, England

[10] Royal Marsden NHS Fdn Trust, Dept Pathol, London SW3 6JJ, England

[11] Royal Marsden NHS Fdn Trust, Dept Urol, London SW3 6JJ, England

[12] Univ Coll London Hosp, Dept Cellular Pathol, London NW1 2BU, England

[13] Royal Marsden Hosp, Ctr Mol Pathol, Translat Immune Oncol Lab, Sutton SM2 5PT, Surrey, England

[14] Biocruces Bizkaia Inst, Cruces Univ Hosp, Dept Pathol, Baracaldo 48903, Bizkaia, Spain

[15] St Thomas Hosp, Guys & St Thomas NHS Fdn Trust, Dept Cellular Pathol, London SE1 7EH, England

[16] Peter MacCallum Canc Ctr, Div Res, Melbourne, Vic 300, Australia

[17] GZA ZNA Hosp, Dept Pathol, Antwerp, Belgium

[18] UCL, Canc Metastasis Lab, Canc Inst, London WC1E 6DD, England

[19] Univ Coll London Hosp, Dept Med Oncol, London NW1 2BU, England

[20] UCL, Div Infect & Immun, London WC1E 6BT, England

[21] UCL, Canc Inst, London WC1E 6DD, England

来源：

CANCER CELL | 2021年 / 39卷 / 11期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

TERTIARY LYMPHOID STRUCTURES; HIGH-DOSE INTERLEUKIN-2; T-CELLS; B-CELLS; SPONTANEOUS REGRESSION; PD-1; BLOCKADE; ACQUIRED-RESISTANCE; PROGNOSTIC IMPACT; PLASMA-CELLS; SOLID TUMORS;

D O I：

10.1016/j.ccell.2021.10.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8(+) T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

引用

页码：1497 / +

页数：34

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