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Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells
Michal A. Stanczak, … , Alfred Zippelius, Heinz Läubli
Michal A. Stanczak, … , Alfred Zippelius, Heinz Läubli
Published August 21, 2018
Citation Information: J Clin Invest. 2018;128(11):4912-4923. https://doi.org/10.1172/JCI120612.
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Research Article Immunology Oncology

Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells

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Abstract

First-generation immune checkpoint inhibitors, including anti–CTLA-4 and anti–programmed death 1 (anti–PD-1) antibodies, have led to major clinical progress, yet resistance frequently leads to treatment failure. Thus, new targets acting on T cells are needed. CD33-related sialic acid–binding immunoglobulin-like lectins (Siglecs) are pattern-recognition immune receptors binding to a range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) that suppress autoimmune responses. Siglecs are expressed at very low levels on normal T cells, and these receptors were not until recently considered as interesting targets on T cells for cancer immunotherapy. Here, we show an upregulation of Siglecs, including Siglec-9, on tumor-infiltrating T cells from non–small cell lung cancer (NSCLC), colorectal, and ovarian cancer patients. Siglec-9–expressing T cells coexpressed several inhibitory receptors, including PD-1. Targeting of the sialoglycan-SAMP/Siglec pathway in vitro and in vivo resulted in increased anticancer immunity. T cell expression of Siglec-9 in NSCLC patients correlated with reduced survival, and Siglec-9 polymorphisms showed association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as a potential target for improving T cell activation for immunotherapy.

Authors

Michal A. Stanczak, Shoib S. Siddiqui, Marcel P. Trefny, Daniela S. Thommen, Kayluz Frias Boligan, Stephan von Gunten, Alexandar Tzankov, Lothar Tietze, Didier Lardinois, Viola Heinzelmann-Schwarz, Michael von Bergwelt-Baildon, Wu Zhang, Heinz-Josef Lenz, Younghun Han, Christopher I. Amos, Mohammedyaseen Syedbasha, Adrian Egli, Frank Stenner, Daniel E. Speiser, Ajit Varki, Alfred Zippelius, Heinz Läubli

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Figure 5

Sialylated SAMPs enhance immune escape and tumor growth in vivo.

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Sialylated SAMPs enhance immune escape and tumor growth in vivo.
(A) Sig...
(A) Siglec-E expression was determined by flow cytometry on control splenocytes, splenocytes from tumor-bearing mice, and CD8+ TILs from subcutaneous MC38 tumors (n = 25–28). Statistical analysis performed by 1-way ANOVA. (B) Expression of intracellular Ki67 was examined by flow cytometry on SigE–CD8+ and SigE+CD8+ TILs (n = 18). Statistical analysis by paired Student’s t test. (C–E) Frequencies of inhibitory immune receptor expression on SigE–CD8+ and SigE+CD8+ TILs from MC38 tumors, as studied by flow cytometry. PD-1 (C, n = 16), TIM-3 (D, n = 18), and LAG-3 (E, n = 7) were analyzed. Statistical analysis by paired Student’s t test. (F) Number of coexpressed inhibitory receptors on SigE–CD8+ or SigE+CD8+ TILs. (G) Upregulation of CD25+CD69+ upon restimulation of sorted SigE–CD8+ and SigE+CD8+ TILs. Statistical analysis by paired Student’s t test. (H) Growth curves of subcutaneous WT or GNE-KO MC38 tumors (n = 8–9). (I) Growth curves of subcutaneous WT and GNE-KO EMT6 tumors (n = 13-14). Experiments were replicated 2 to 3 times. Statistical analysis by 2-way ANOVA. (J and K) Frequencies of CD3+ and CD8+ cells in the tumor (n = 7). Statistical analysis by unpaired Student’s t test. **P < 0.01; ***P < 0.001. Data are presented as mean ± SD.

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