TIGIT contributes to the regulation of 4-1BB and does not define NK cell dysfunction in glioblastoma

Kyle B Lupo; Sandra Torregrosa-Allen; Bennett D Elzey; Sagar Utturkar; Nadia A Lanman; Aaron A Cohen-Gadol; Veronika Slivova; MacKenzie McIntosh; Karen E Pollok; Sandro Matosevic

doi:10.1016/j.isci.2023.108353

TIGIT contributes to the regulation of 4-1BB and does not define NK cell dysfunction in glioblastoma

iScience. 2023 Oct 28;26(12):108353. doi: 10.1016/j.isci.2023.108353. eCollection 2023 Dec 15.

Authors

Kyle B Lupo¹, Sandra Torregrosa-Allen², Bennett D Elzey^{2

3

4}, Sagar Utturkar², Nadia A Lanman^{2

3}, Aaron A Cohen-Gadol⁵, Veronika Slivova⁶, MacKenzie McIntosh⁷, Karen E Pollok^{8

9

10

11}, Sandro Matosevic^{1

2}

Affiliations

¹ Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, USA.
² Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
³ Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA.
⁴ Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Department of Neurological Surgery, Indiana University, Indianapolis, IN, USA.
⁶ Enterprise Clinical Research Operations Biorepository, Indiana University Health, Indianapolis, IN 46202, USA.
⁷ Histology Research Laboratory, Center for Comparative Translational Research, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA.
⁸ In Vivo Therapeutics Core, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
⁹ Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
¹¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.

Abstract

TIGIT is a receptor on human natural killer (NK) cells. Here, we report that TIGIT does not spontaneously induce inhibition of NK cells in glioblastoma (GBM), but rather acts as a decoy-like receptor, by usurping binding partners and regulating expression of NK activating ligands and receptors. Our data show that in GBM patients, one of the underpinnings of unresponsiveness to TIGIT blockade is that by targeting TIGIT, NK cells do not lose an inhibitory signal, but gains the potential for new interactions with other, shared, TIGIT ligands. Therefore, TIGIT does not define NK cell dysfunction in GBM. Further, in GBM, TIGIT⁺ NK cells are hyperfunctional. In addition, we discovered that 4-1BB correlates with TIGIT expression, the agonism of which contributes to TIGIT immunotherapy. Overall, our data suggest that in GBM, TIGIT acts as a regulator of a complex network, and provide new clues about its use as an immunotherapeutic target.

Keywords: Biological sciences; Cancer; Health sciences; Immunology.

Abstract

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