Barras, Ghsoni, and Chiffelle et al. performed comprehensive single-cell and spatial profiling of longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, and identified pre-existing cellular networks in the TME and tumor mutational burden that associated with clinical response to TIL-ACT. At baseline, responders showed rich intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Effective TIL-ACT restored the TIL repertoire and reprogrammed the tumor macrophage population toward CXCL9+ cells, thereby strengthening the potential CD8+ T cell:myeloid interactome.
Contributed by Shishir Pant
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.
Author Info: (1) Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, University of Lausanne (UNIL) and Lausanne University Hospital (CHUV), Agora Cancer Research Cent
Author Info: (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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (2) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (3) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (4) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (5) Unit of Translational Oncopathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland. (6) 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. (7) 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. (8) 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. (9) 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. (10) 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. (11) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (12) Department of Radiology and Interventional Radiology, Lausanne University Hospital, Lausanne, Switzerland. (13) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (14) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (15) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (16) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (17) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (18) Flow Cytometry Facility, Department of Formation and Research, University of Lausanne, Epalinges, Switzerland. (19) Scientific Research Consulting Hellas, Athens, Greece. (20) Scientific Research Consulting Hellas, Athens, Greece. (21) 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. Service of Radiation Oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (22) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (23) Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. (24) Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. (25) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (26) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (27) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Department of Oncology, Center of Experimental Therapeutics, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. (28) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (29) Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Lausanne, Switzerland. (30) Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Lausanne, Switzerland. (31) Department of Visceral Surgery, Lausanne University Hospital, and University of Lausanne, Lausannne, Switzerland. (32) Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. (33) Department of Radiology and Interventional Radiology, Lausanne University Hospital, Lausanne, Switzerland. (34) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (35) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Department of Oncology, Center of Experimental Therapeutics, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. (36) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Department of Oncology, Center of Experimental Therapeutics, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland. (37) 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. Biomedical Data Science Center and Swiss Institute of Bioinformatics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. (38) 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. Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. (39) Unit of Translational Oncopathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland. (40) 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. Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. (41) Faculty of Nursing, National and Kapodistrian University of Athens, Athens, Greece. (42) Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. (43) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (44) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. (45) 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. Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland. Service of Immuno-oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
