Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors

被引：98

作者：

Burger, Megan L. ^{[1
]}

Cruz, Amanda M. ^{[1
,2
]}

Crossland, Grace E. ^{[1
]}

Gaglia, Giorgio ^{[3
,4
,5
]}

Ritch, Cecily C. ^{[3
,4
,5
]}

Blatt, Sarah E. ^{[1
]}

Bhutkar, Arjun ^{[1
]}

Canner, David ^{[1
,2
]}

Kienka, Tamina ^{[1
]}

Tavana, Sara Z. ^{[1
]}

Barandiaran, Alexia L. ^{[1
]}

Garmilla, Andrea ^{[1
]}

Schenkel, Jason M. ^{[1
,3
]}

Hillman, Michelle ^{[1
]}

Kobara, Izumi de los Rios ^{[1
]}

Li, Amy ^{[1
,2
]}

Jaeger, Alex M. ^{[1
]}

Hwang, William L. ^{[1
,6
,7
]}

Westcott, Peter M. K. ^{[1
]}

Manos, Michael P. ^{[8
,9
,10
]}

Holovatska, Marta M. ^{[8
,9
,10
]}

Hodi, F. Stephen ^{[8
,9
,10
,11
]}

Regev, Aviv ^{[1
,2
,6
,12
]}

Santagata, Sandro ^{[3
,4
,5
,13
]}

Jacks, Tyler ^{[1
,2
]}

机构：

[1] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] MIT, Dept Biol, Cambridge, MA 02139 USA

[3] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[4] Harvard Med Sch, Ludwig Ctr Harvard, Boston, MA 02115 USA

[5] Harvard Med Sch, Dept Syst Biol, Lab Syst Pharmacol, Boston, MA 02115 USA

[6] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[7] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA

[8] Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02215 USA

[9] Harvard Med Sch, Boston, MA 02215 USA

[10] Dana Farber Canc Inst, Ctr Immunooncol, Boston, MA 02215 USA

[11] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[12] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

[13] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02215 USA

来源：

CELL | 2021年 / 184卷 / 19期

关键词：

NEOANTIGEN LANDSCAPE; CHECKPOINT BLOCKADE; LUNG-CANCER; MELANOMA; IMMUNOTHERAPY; PEPTIDE; DIFFERENTIATION; IMMUNODOMINANCE; REGULATORS; EXPRESSION;

D O I：

10.1016/j.cell.2021.08.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1(+) progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1(+) cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6(+) TCF1(+) cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6(+) TCF1(+) cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

引用

页码：4996 / +

页数：45

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