Proteomics of immune cells from liver tumors reveals immunotherapy targets

Fernando P Canale; Julia Neumann; Janusz von Renesse; Elisabetta Loggi; Matteo Pecoraro; Ian Vogel; Giada Zoppi; Gaia Antonini; Tobias Wolf; Wenjie Jin; Xiaoqin Zheng; Giuliano La Barba; Emrullah Birgin; Marianne Forkel; Tobias Nilsson; Romina Marone; Henrik Mueller; Nadege Pelletier; Lukas T Jeker; Gianluca Civenni; Christoph Schlapbach; Carlo V Catapano; Lena Seifert; Adrian M Seifert; Silke Gillessen; Sara De Dosso; Alessandra Cristaudi; Nuh N Rahbari; Giorgio Ercolani; Roger Geiger

doi:10.1016/j.xgen.2023.100331

Proteomics of immune cells from liver tumors reveals immunotherapy targets

Cell Genom. 2023 May 30;3(6):100331. doi: 10.1016/j.xgen.2023.100331. eCollection 2023 Jun 14.

Authors

Fernando P Canale^{1

2}, Julia Neumann^{1

2}, Janusz von Renesse^{3

4}, Elisabetta Loggi⁵, Matteo Pecoraro^{1

2}, Ian Vogel^{1

2}, Giada Zoppi^{1

2}, Gaia Antonini^{1

2}, Tobias Wolf^{1

2}, Wenjie Jin^{1

2}, Xiaoqin Zheng^{1

2}, Giuliano La Barba⁶, Emrullah Birgin⁷, Marianne Forkel⁸, Tobias Nilsson⁸, Romina Marone^{9

10}, Henrik Mueller⁸, Nadege Pelletier⁸, Lukas T Jeker^{9

10}, Gianluca Civenni^{2

11}, Christoph Schlapbach¹², Carlo V Catapano^{2

11}, Lena Seifert^{3

4}, Adrian M Seifert^{3

4}, Silke Gillessen^{2

13}, Sara De Dosso^{2

13}, Alessandra Cristaudi¹⁴, Nuh N Rahbari⁷, Giorgio Ercolani^{15

16}, Roger Geiger^{1

2

11}

Affiliations

¹ Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland.
² Università della Svizzera italiana (USI), Lugano, Switzerland.
³ Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁴ National Center for Tumor Diseases (NCT), Dresden, Germany.
⁵ Hepatology Unit, Department of Medical & Surgical Sciences, University of Bologna, Bologna, Italy.
⁶ General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy.
⁷ Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany.
⁸ Roche Pharma Research and Early Development, Infectious Diseases Discovery, Roche Innovation Center Basel, Basel, Switzerland.
⁹ Department of Biomedicine, University of Basel, Basel, Switzerland.
¹⁰ Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland.
¹¹ Institute of Oncology Research (IOR), Bellinzona, Switzerland.
¹² Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹³ Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland.
¹⁴ Department of General and Visceral Surgery, Cantonal Hospital Lugano, Lugano, Switzerland.
¹⁵ Department of Medical and Surgical Sciences - DIMEC; Alma Mater Studiorum - Univeristy of Bologna, Bologna, Italy.
¹⁶ Morgagni-Pierantoni Hospital, Ausl Romagna, Forlì, Italy.

Abstract

Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well as monocyte/macrophages, CD4⁺ and CD8⁺ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8⁺ T cells in tumors. Ablation of AFAP1L2 in CD8⁺ T cells increased their viability upon repeated stimulation and enhanced their anti-tumor activity synergistically with PD-L1 blockade in mouse models. Our data reveal new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer.

Keywords: CRISPR in mouse T cells; HCC; NK cells; T cells; cancer immunotherapy; liver cancer; macrophages; mass spectrometry-based proteomics; profiles of tumor-infiltrating immune cells; proteomes.