To improve the antitumor efficacy of TEGs (αβ T cells engineered to express a defined γδ TCR) Hernández-López and Van Diest et al. evaluated various engineered chimeric co-stimulatory receptors to co-target cancer-associated stress antigens. Certain NKG2D costimulatory variations enhanced γ9δ2TCR TEGs in vitro and in vivo, with different dynamics, but were limited by competition with endogenous NKG2D on CD8+ T cells. Expression of a coreceptor comprising an anti-CD277 extracellular domain and a 4-1BB intracellular domain avoided this competitive effect, reprogramming both CD4+ and CD8+ TEGs and mediating control of both liquid and solid tumors in mice.
Contributed by Lauren Hitchings
ABSTRACT: Few cancers can be targeted efficiently by engineered T cell strategies. Here, we show that γδ T cell antigen receptor (γδ TCR)-mediated cancer metabolome targeting can be combined with targeting of cancer-associated stress antigens (such as NKG2D ligands or CD277) through the addition of chimeric co-receptors. This strategy overcomes suboptimal γ9δ2 TCR engagement of αβ T cells engineered to express a defined γδ TCR (TEGs) and improves serial killing, proliferation and persistence of TEGs. In vivo, the NKG2D-CD28WT chimera enabled control only of liquid tumors, whereas the NKG2D-4-1BBCD28TM chimera prolonged persistence of TEGs and improved control of liquid and solid tumors. The CD277-targeting chimera (103-4-1BB) was the most optimal co-stimulation format, eradicating both liquid and solid tumors. Single-cell transcriptomic analysis revealed that NKG2D-4-1BBCD28TM and 103-4-1BB chimeras reprogram TEGs through NF-κB. Owing to competition with naturally expressed NKG2D in CD8+ TEGs, the NKG2D-4-1BBCD28TM chimera mainly skewed CD4+ TEGs toward adhesion, proliferation, cytotoxicity and less exhausted signatures, whereas the 103-4-1BB chimera additionally shaped the CD8+ subset toward a proliferative state.
Author Info: (1) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (2) Center for Translational Immunology, University Medica
Author Info: (1) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (2) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (3) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (4) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (5) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (6) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (7) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. Department of Experimental and Clinical Medicine, Magna Gr¾cia University, Catanzaro, Italy. (8) Faculty of Biology, University of Freiburg, Freiburg, Germany. Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany. (9) Faculty of Biology, University of Freiburg, Freiburg, Germany. Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany. (10) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (11) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (12) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (13) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (14) Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands. (15) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (16) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (17) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (18) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands. Roche Pharmaceutical Research and Early Development, Basel, Switzerland. (19) Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands. (20) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (21) Princess Mxima Center for Pediatric Oncology, Utrecht, the Netherlands. (22) Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands. (23) Faculty of Biology, University of Freiburg, Freiburg, Germany. Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany. (24) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (25) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. (26) Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. j.h.e.kuball@umcutrecht.nl. Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands. j.h.e.kuball@umcutrecht.nl.
