Based on shifted Poisson statistics, Salazar-Cavazos et al. developed the StoICS pipeline and found that stochastic activation of rare “spark T cells” – CD5lowC11ahigh in mice and CCR7lowCD45ROhigh in humans – accounts for variable cancer immunotherapy outcomes, even when immunological settings appear identical. Spark T cells demonstrate a distinct chromatin accessibility map and can rapidly produce IFNγ (and other cytokines) upon TCR triggering, which entrains neighboring T cells and decides the overall immunotherapeutic outcome. An ENTPD1highCD2high gene signature in human spark T cells predicted response to anti-CTLA-4 treatment.
Contributed by Ute Burkhardt
ABSTRACT: Cancer immunotherapies trigger highly variable responses in patients and in genetically identical mouse models. To assess the intrinsic stochasticity of these therapies, we performed thousands of well-controlled ex vivo immunoassays. We show that leukocyte responses and tumor cytotoxicity are highly variable at the macroscopic level and statistically distributed as a shifted Poisson process. Stochastic activation of a rare subpopulation of T cells (so-called Spark T cells), coupled with a paracrine interferon (IFN)-_-driven positive feedback, accounts for this measured "noise" in immunotherapeutic reactions. We integrated these quantitative insights into a custom-designed machine-learning pipeline to analyze immune reactions with single-cell resolution. This led us to phenotypically and functionally identify Spark T cells in murine naive T cells and in human T cell blasts as prepared for adoptive T cell therapy. We then demonstrate their relevance in explaining variable outcomes in cancer immunotherapies.
Author Info: (1) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (2) Immunodynamics Group, Laborator
Author Info: (1) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (2) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (3) Inserm U1330 and Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France; Inserm U932, Institut Curie, PSL Research University, 75005 Paris, France. (4) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (5) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (6) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (7) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (8) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (9) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (10) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (11) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. (12) Inserm U1330 and Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France. (13) Department of Mechanical Engineering, University of Maryland, College Park, MD, USA. (14) Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: gregoire.altan-bonnet@nih.gov.
