Glial TIM-3 Modulates Immune Responses in the Brain Tumor Microenvironment

被引:29
作者
Kim, Hyung-Seok [1 ,2 ]
Chang, Chi Young [2 ]
Yoon, Hee Jung [2 ]
Kim, Ki Sun [1 ,2 ]
Koh, Han Seok [2 ]
Kim, Sang Soo [3 ]
Lee, Sang-Jin [1 ,2 ]
Kane, Lawrence P. [4 ]
Park, Eun Jung [1 ,2 ]
机构
[1] Natl Canc Ctr, Grad Sch Canc Sci & Policy, Dept Canc Biomed Sci, Goyang Si, Gyeonggi Do, South Korea
[2] Natl Canc Ctr, Canc Immunol Branch, Goyang Si, Gyeonggi Do, South Korea
[3] Natl Canc Ctr, Fus Technol Res Branch, Goyang Si, Gyeonggi Do, South Korea
[4] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA
基金
新加坡国家研究基金会;
关键词
EXPRESSION; CANCER; CELLS; CHECKPOINT; THERAPY; IMMUNOTHERAPY; INFLAMMATION; MACROPHAGES; AUTOIMMUNE; ANTI-TIM-3;
D O I
10.1158/0008-5472.CAN-19-2834
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3), a potential immunotherapeutic target for cancer, has been shown to display diverse characteristics in a context-dependent manner. Thus, it would be useful to delineate the precise functional features of TIM-3 in a given situation. Here, we report that glial TIM-3 shows distinctive properties in the brain tumor microenvironment. TIM-3 was expressed on both growing tumor cells and their surrounding cells including glia and T cells in an orthotopic mouse glioma model. The expression pattern of TIM-3 was distinct from those of other immune checkpoint molecules in tumor-exposed and tumor-infiltrating glia. Comparison of cells from tumor-bearing and contralateral hemispheres of a glioma model showed that TIM-3 expression was lower in tumor-infiltrating CD11b+CD45(mid) glial cells but higher in tumor-infiltrating CD8(+) T cells. In TIM-3 mutant mice with intracellular signaling defects and Cre- inducible TIM-3 mice, TIM-3 affected the expression of several immune-associated molecules including iNOS and PD-L1 in primary glia-exposed conditioned media (CM) from brain tumors. Further, TIM-3 was cross-regulated by TLR2, but not by TLR4, in brain tumor CM- or Pam(3)CSK(4)-exposed glia. In addition, following exposure to tumor CM, IFN gamma production was lower in T cells cocultured with TIM-3-defective glia than with normal glia. Collectively, these findings suggest that glial TIM-3 actively and distinctively responds to brain tumor, and plays specific intracellular and intercellular immunoregulatory roles that might be different from TIM-3 on T cells in the brain tumor microenvironment. Significance: TIM-3 is typically thought of as a T-cell checkpoint receptor. This study demonstrates a role for TIM-3 in mediating myeloid cell responses in glioblastoma.
引用
收藏
页码:1833 / 1845
页数:13
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