Intratumoral T cell activation kills tumors regardless of T cell specificity
(1) Ghirardelli Smith OC (2) Dao TT (3) Gavil NV (4) O'Flanagan SD (5) Rubin AJ (6) Nguyen S (7) Watowich MB (8) Liu N (9) Weyu E (10) Quarnstrom CF (11) Soerens AG (12) Joag V (13) Rosato PC (14) Krummel MF (15) Geller MA (16) Miller JS (17) Giubellino A (18) Vezys V (19) Shalek AK (20) Masopust D
Smith, Dao, and Gavil et al. showed that activation of unexhausted non-tumor-specific memory T cells in the TIME induced tumor clearance in the absence of NK cell- or TCRαβ-dependent tumor cell recognition, although the latter was required to protect from dLN metastases after primary tumor surgical resection. Expression of IFNγ, TNF, and NO by T and myeloid cells, dependent on endothelial cell VCAM-1 upregulation, induced caspase-dependent apoptosis of primary tumor cells, which was boosted by anti-PD-L1. Gene expression analyses indicated that these antitumor mechanisms also occurred in human patients with melanoma with favorable prognoses.
Contributed by Paula Hochman
(1) Ghirardelli Smith OC (2) Dao TT (3) Gavil NV (4) O'Flanagan SD (5) Rubin AJ (6) Nguyen S (7) Watowich MB (8) Liu N (9) Weyu E (10) Quarnstrom CF (11) Soerens AG (12) Joag V (13) Rosato PC (14) Krummel MF (15) Geller MA (16) Miller JS (17) Giubellino A (18) Vezys V (19) Shalek AK (20) Masopust D
Smith, Dao, and Gavil et al. showed that activation of unexhausted non-tumor-specific memory T cells in the TIME induced tumor clearance in the absence of NK cell- or TCRαβ-dependent tumor cell recognition, although the latter was required to protect from dLN metastases after primary tumor surgical resection. Expression of IFNγ, TNF, and NO by T and myeloid cells, dependent on endothelial cell VCAM-1 upregulation, induced caspase-dependent apoptosis of primary tumor cells, which was boosted by anti-PD-L1. Gene expression analyses indicated that these antitumor mechanisms also occurred in human patients with melanoma with favorable prognoses.
Contributed by Paula Hochman
ABSTRACT: Immunotherapies putatively require tumor-specific T cells. Here we show how T cells can eliminate tumors without tumor specificity via paracrine signaling. Activating unexhausted bystander non-tumor-specific T cells within tumors resulted in tumor elimination without conventional recognition-dependent mechanisms and in the absence of any tumor-specific T cell receptor (TCR)αβ+ T cells. Robust T cell activation recruited immune cells, used innate leukocytes and triggered a tumoricidal combination of effector molecules and panoptotic pathways. Mechanistically, interferon-γ, tumor necrosis factor and nitric oxide induced caspase-dependent death, recapitulating melanoma clearance in mice or human melanoma cell death in vitro. Gene expression signatures associated with this response in mice were predictive of survival among human patients with melanoma. Thus, triggering productive T cell activation within tumors can be sufficient for immunotherapy, without needing to induce or rescue cancer-specific responses.
Author Info:
(1) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. Center for Immunology, University of Minnesota Medical School, Minneapo
lis, MN, USA. (2) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (4) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (5) Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Biology and Program in Biochemistry, Bowdoin College, Brunswick, ME, USA. (7) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (8) Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (10) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (11) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (12) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (13) Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth College, Dartmouth Cancer Center, Lebanon, NH, USA. (14) Department of Pathology, University of California San Francisco, San Francisco, CA, USA. (15) Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN, USA. (16) Department of Medicine, University of Minnesota, Minneapolis, MN, USA. (17) Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. (18) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (19) Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (20) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. masopust@umn.edu. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. masopust@umn.edu.
