Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8 + T-myeloid cell networks in melanoma

Author:

Barras David12ORCID,Ghisoni Eleonora123ORCID,Chiffelle Johanna12ORCID,Orcurto Angela23,Dagher Julien4ORCID,Fahr Noémie1ORCID,Benedetti Fabrizio1ORCID,Crespo Isaac1,Grimm Alizée J.1,Morotti Matteo1ORCID,Zimmermann Stefan23,Duran Rafael5ORCID,Imbimbo Martina23ORCID,de Olza Maria Ochoa23ORCID,Navarro Blanca23,Homicsko Krisztian123ORCID,Bobisse Sara12ORCID,Labes Danny6,Tsourti Zoe7,Andriakopoulou Charitini7,Herrera Fernanda18,Pétremand Rémy12ORCID,Dummer Reinhard9ORCID,Berthod Gregoire10ORCID,Kraemer Anne I.12,Huber Florian12,Thevenet Jonathan211ORCID,Bassani-Sternberg Michal12ORCID,Schaefer Niklaus12,Prior John O.12ORCID,Matter Maurice13ORCID,Aedo Veronica10ORCID,Dromain Clarisse5ORCID,Corria-Osorio Jesus12ORCID,Tissot Stéphanie211ORCID,Kandalaft Lana E.1211ORCID,Gottardo Raphael114ORCID,Pittet Mikaël115ORCID,Sempoux Christine4ORCID,Michielin Olivier110,Dafni Urania16ORCID,Trueb Lionel23,Harari Alexandre12ORCID,Laniti Denarda Dangaj12ORCID,Coukos George123ORCID

Affiliation:

1. Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, University of Lausanne (UNIL) and Lausanne University Hospital (CHUV), Agora Cancer Research Center, Lausanne, Switzerland.

2. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland.

3. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.

4. Unit of Translational Oncopathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland.

5. Department of Radiology and Interventional Radiology, Lausanne University Hospital, Lausanne, Switzerland.

6. Flow Cytometry Facility, Department of Formation and Research, University of Lausanne, Epalinges, Switzerland.

7. Scientific Research Consulting Hellas, Athens, Greece.

8. Service of Radiation Oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.

9. Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

10. Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

11. Department of Oncology, Center of Experimental Therapeutics, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.

12. Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Lausanne, Switzerland.

13. Department of Visceral Surgery, Lausanne University Hospital, and University of Lausanne, Lausannne, Switzerland.

14. Biomedical Data Science Center and Swiss Institute of Bioinformatics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

15. Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.

16. Faculty of Nursing, National and Kapodistrian University of Athens, Athens, Greece.

Abstract

Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8 + TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine,Immunology

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