Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy

被引：132

作者：

Somasundaram, Rajasekharan ^{[1
]}

Connelly, Thomas ^{[1
]}

Choi, Robin ^{[1
]}

Choi, Hyeree ^{[1
]}

Samarkina, Anastasia ^{[1
]}

Ling Li ^{[1
]}

Gregorio, Elizabeth ^{[1
]}

Chen, Yeqing ^{[1
]}

Thakur, Rohit ^{[2
]}

Abdel-Mohsen, Mohamed ^{[1
]}

Beqiri, Marilda ^{[1
]}

Kiernan, Meaghan ^{[1
]}

Perego, Michela ^{[1
]}

Fang Wang ^{[1
]}

Min Xiao ^{[1
]}

Brafford, Patricia ^{[1
]}

Xue Yang ^{[1
]}

Xu, Xiaowei ^{[3
]}

Secreto, Anthony ^{[4
]}

Danet-Desnoyers, Gwenn ^{[4
]}

Traum, Daniel ^{[5
,6
]}

Kaestner, Klaus H. ^{[5
,6
]}

Huang, Alexander C. ^{[3
]}

Hristova, Denitsa ^{[1
]}

Wang, Joshua ^{[1
]}

Fukunaga-Kalabis, Mizuho ^{[1
]}

Krepler, Clemens ^{[1
]}

Fang Ping-Chen ^{[1
]}

Zhou, Xiangyang ^{[1
]}

Gutierrez, Alexis ^{[1
]}

Rebecca, Vito W. ^{[1
]}

Vonteddu, Prashanthi ^{[1
]}

Dotiwala, Farokh ^{[1
]}

Bala, Shashi ^{[1
]}

Majumdar, Sonali ^{[1
]}

Dweep, Harsh ^{[1
]}

Wickramasinghe, Jayamanna ^{[1
]}

Kossenkov, Andrew, V ^{[1
]}

Reyes-Arbujas, Jorge ^{[1
]}

Santiago, Kenisha ^{[1
]}

Nguyen, Tran ^{[1
]}

Griss, Johannes ^{[7
]}

Keeney, Frederick ^{[1
]}

Hayden, James ^{[1
]}

Gavin, Brian J. ^{[1
]}

Weiner, David ^{[1
]}

Montaner, Luis J. ^{[1
]}

Qin Liu ^{[1
]}

Peiffer, Lukas ^{[8
]}

Becker, Juergen ^{[8
]}

机构：

[1] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA

[2] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[3] Univ Penn, Dept Pathol & Med, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept Med, Stem Cell & Xenograft Core, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA

[7] Med Univ Vienna, Dept Dermatol, Div Immunol Allergy & Infect Dis DIAID, Vienna, Austria

[8] Univ Duisburg Essen, Essen, Germany

[9] MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX USA

[10] Univ Calif San Francisco, Dept Melanoma Med Oncol, San Francisco, CA 94143 USA

[11] Univ Calif San Francisco, Dept Pathol & Dermatol, San Francisco, CA 94143 USA

[12] AstraZeneca, Gaithersburg, MD USA

[13] GeneOne Life Sci Inc, Ft Washington, PA USA

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

关键词：

IMMUNE CELLS; CANCER; MECHANISMS; EXPRESSION; EFFICACY;

D O I：

10.1038/s41467-020-20600-7

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：

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34(+) cells and implanting autologous thymus in immune-deficient NOD-scid IL2R gamma(null) (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3(+) Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8(+)/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3(+) Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

引用

页数：14

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