Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

Marcel P Trefny; Nicole Kirchhammer; Priska Auf der Maur; Marina Natoli; Dominic Schmid; Markus Germann; Laura Fernandez Rodriguez; Petra Herzig; Jonas Lötscher; Maryam Akrami; Jane C Stinchcombe; Michal A Stanczak; Andreas Zingg; Melanie Buchi; Julien Roux; Romina Marone; Leyla Don; Didier Lardinois; Mark Wiese; Lukas T Jeker; Mohamed Bentires-Alj; Jérémie Rossy; Daniela S Thommen; Gillian M Griffiths; Heinz Läubli; Christoph Hess; Alfred Zippelius

doi:10.1038/s41467-022-35583-w

Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

Nat Commun. 2023 Feb 2;14(1):86. doi: 10.1038/s41467-022-35583-w.

Authors

Marcel P Trefny¹, Nicole Kirchhammer², Priska Auf der Maur³, Marina Natoli², Dominic Schmid², Markus Germann², Laura Fernandez Rodriguez², Petra Herzig², Jonas Lötscher⁴, Maryam Akrami², Jane C Stinchcombe⁵, Michal A Stanczak⁶, Andreas Zingg⁶, Melanie Buchi², Julien Roux^{7

8}, Romina Marone^{9

10}, Leyla Don², Didier Lardinois¹¹, Mark Wiese¹¹, Lukas T Jeker^{9

10}, Mohamed Bentires-Alj³, Jérémie Rossy¹², Daniela S Thommen^{2

13}, Gillian M Griffiths⁵, Heinz Läubli^{6

14}, Christoph Hess^{4

15}, Alfred Zippelius^{16

17}

Affiliations

¹ Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland. [email protected].
² Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
³ Laboratory of Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
⁴ Laboratory of Immunobiology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
⁵ Cambridge Institute for Medical Research, Biomedical Campus, Cambridge, CB2 0XY, UK.
⁶ Laboratory of Cancer Immunotherapy, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
⁷ Bioinformatics Core Facility, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
⁸ Swiss Institute of Bioinformatics, Basel, Switzerland.
⁹ Laboratory of Molecular Immune Regulation, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
¹⁰ Transplantation Immunology & Nephrology, Basel University Hospital, Basel, Switzerland.
¹¹ Department of Surgery, University Hospital Basel, Basel, Switzerland.
¹² Biotechnology Institute Thurgau, University of Konstanz, Kreuzlingen, Switzerland.
¹³ Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹⁴ Medical Oncology, University Hospital Basel, Basel, Switzerland.
¹⁵ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, CB2 0AW, UK.
¹⁶ Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland. [email protected].
¹⁷ Medical Oncology, University Hospital Basel, Basel, Switzerland. [email protected].

Abstract

Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca²⁺, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Humans
Immunotherapy
Lymphocytes, Tumor-Infiltrating
Neoplasms*
T-Cell Exhaustion*