Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer

被引:111
作者
Sceneay, Jaclyn [1 ,2 ]
Goreczny, Gregory J. [1 ,2 ]
Wilson, Kristin [1 ]
Morrow, Sara [1 ]
DeCristo, Molly J. [1 ,2 ]
Ubellacker, Jessalyn M. [1 ,2 ]
Qin, Yuanbo [1 ,2 ]
Laszewski, Tyler [1 ]
Stover, Daniel G. [3 ]
Barrera, Victor [4 ]
Hutchinson, John N. [4 ]
Freedman, Rachel A. [5 ,6 ]
Mittendorf, Elizabeth A. [6 ,7 ]
McAllister, Sandra S. [1 ,2 ,8 ,9 ]
机构
[1] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA
[2] Harvard Med Sch, Dept Med, Boston, MA 02115 USA
[3] Ohio State Univ, Ctr Comprehens Canc, Div Med Oncol, Columbus, OH 43210 USA
[4] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA
[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[6] Dana Farber Brigham & Womens Canc Ctr, Breast Oncol Program, Boston, MA USA
[7] Brigham & Womens Hosp, Dept Surg, Div Breast Surg, 75 Francis St, Boston, MA 02115 USA
[8] Broad Inst Harvard & MIT, Cambridge, MA USA
[9] Harvard Stem Cell Inst, Cambridge, MA USA
关键词
TUMOR-INFILTRATING LYMPHOCYTES; HEMATOPOIETIC STEM-CELLS; MAMMARY-CARCINOMA; OLDER PATIENTS; PD-1; BLOCKADE; EXPRESSION; NIVOLUMAB; DOCETAXEL; MECHANISM; INHIBITORS;
D O I
10.1158/2159-8290.CD-18-1454
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Immune checkpoint blockade (ICB) therapy, which targets T cell-inhibitory receptors, has revolutionized cancer treatment. Among the breast cancer subtypes, evaluation of ICB has been of greatest interest in triple-negative breast cancer (TNBC) due to its immunogenicity, as evidenced by the presence of tumor-infiltrating lymphocytes and elevated PD-L1 expression relative to other subtypes. TNBC incidence is equally distributed across the age spectrum, affecting 10% to 15% of women in all age groups. Here we report that increased immune dysfunction with age limits ICB efficacy in aged TNBC-bearing mice. The tumor microenvironment in both aged mice and patients with TNBC shows decreased IFN signaling and antigen presentation, suggesting failed innate immune activation with age. Triggering innate immune priming with a STING agonist restored response to ICB in aged mice. Our data implicate age-related immune dysfunction as a mechanism of ICB resistance in mice and suggest potential prognostic utility of assessing IFN-related genes in patients with TNBC receiving ICB therapy. SIGNIFICANCE. These data demonstrate for the first time that age determines the T cell-inflamed phenotype in TNBC and affects response to ICB in mice. Evaluating IFN-related genes from tumor genomic data may aid identification of patients for whom combination therapy including an IFN pathway activator with ICB may be required.
引用
收藏
页码:1208 / 1227
页数:20
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