Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer

被引：1

作者：

Ma, Ying ^{[1
,2
,3
]}

Zhao, Xiangqin ^{[1
]}

Feng, Jingyan ^{[4
]}

Qiu, Suimin ^{[5
]}

Ji, Baoan ^{[6
]}

Huang, Lu ^{[2
]}

Hwu, Patrick ^{[7
]}

Logsdon, Craig D. ^{[8
,9
]}

Wang, Huamin ^{[10
,11
]}

机构：

[1] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Tianjins Clin Res Ctr Canc, Dept Pancreat Canc,Key Lab Canc Prevent & Therapy, Tianjin 300060, Peoples R China

[2] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Immunol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[4] GRIMED Co Ltd, Beijing 102200, Peoples R China

[5] Univ Texas Med Branch, Dept Surg, 301 Univ Blvd, Galveston, TX 77555 USA

[6] Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA

[7] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Pathol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[11] Univ Texas Grad Sch Biomed Sci Houston, Houston, TX 77030 USA

来源：

ISCIENCE | 2024年 / 27卷 / 11期

基金：

中国国家自然科学基金;

关键词：

OX40; MASITINIB; EXPRESSION; EXPANSION; PATHWAY; GROWTH; MODEL;

D O I：

10.1016/j.isci.2024.111085

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：

Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive tumor microenvironment (TME) contributing to its therapeutic resistance. Following our previous studies, we report that mast cells infiltrating the PDAC TME foster this immunosuppression and desmoplasia. Mast cell infiltration correlated with human PDAC progression, and genetic or pharmacological mast cell depletion reduced tumor growth and desmoplasia while enhancing survival in mouse PDAC models. Mechanistically, mast cell- derived IL-10 promoted PDAC progression. Strikingly, combining an agonistic anti-OX40 immunotherapy with mast cell blockade synergistically elicited durable anti-tumor immunity, marked by increased infiltration of CD8+ + T effector cells expressing granzyme B and dramatic survival benefit unachievable with either approach alone. An OX40-associated gene signature correlated with improved survival in human PDAC, supporting therapeutic translation. Our findings establish mast cells as promoters of the suppressive PDAC TME and rational targets for combination immunotherapy. Targeting this mast cell-mediated resistance mechanism could overcome immunotherapy failure in PDAC.

引用

页数：15

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