γδ T cells modulate anti-tumor immunity in small cell lung cancer
(1) Ng J (2) You Y (3) Zhang TZ (4) Hess JB (5) Best SA (6) Caneborg A (7) Schmiel M (8) Diepstraten ST (9) Spelman T (10) Gray JI (11) Godfrey DI (12) Wu Y (13) Tothill RW (14) Anttila CJA (15) Baldwin TM (16) Naik SH (17) Amann-Zalcenstein D (18) Kersbergen AJ (19) Leong TL (20) George J (21) Ritchie ME (22) Gherardin NA (23) Koay HF (24) Hickey PF (25) Steinfort D (26) Sutherland KD
Using scRNA sequencing, Ng et al. compared LN biopsy samples (non-affected vs. tumor-affected) from SCLC patients to study the antitumor role of MHC-I-independent pathways. Despite being PD-1+, γδ T cells were cytotoxic, infiltrated patient samples, and predicted better outcomes with anti-PD-L1 in patients with high levels of γδ T cells. In preclinical models, γδ T cells were as effective as CD8+ T cells in tarlatamab (DLL3–CD3 BiTE)-redirected SCLC killing, while zoledronate sensitized SCLC cells to Vδ2+ T cell-mediated killing and promoted spontaneous γδ T cell-mediated MHC-I-independent SCLC killing that required BTN2A1.
Contributed by Katherine Turner
(1) Ng J (2) You Y (3) Zhang TZ (4) Hess JB (5) Best SA (6) Caneborg A (7) Schmiel M (8) Diepstraten ST (9) Spelman T (10) Gray JI (11) Godfrey DI (12) Wu Y (13) Tothill RW (14) Anttila CJA (15) Baldwin TM (16) Naik SH (17) Amann-Zalcenstein D (18) Kersbergen AJ (19) Leong TL (20) George J (21) Ritchie ME (22) Gherardin NA (23) Koay HF (24) Hickey PF (25) Steinfort D (26) Sutherland KD
Using scRNA sequencing, Ng et al. compared LN biopsy samples (non-affected vs. tumor-affected) from SCLC patients to study the antitumor role of MHC-I-independent pathways. Despite being PD-1+, γδ T cells were cytotoxic, infiltrated patient samples, and predicted better outcomes with anti-PD-L1 in patients with high levels of γδ T cells. In preclinical models, γδ T cells were as effective as CD8+ T cells in tarlatamab (DLL3–CD3 BiTE)-redirected SCLC killing, while zoledronate sensitized SCLC cells to Vδ2+ T cell-mediated killing and promoted spontaneous γδ T cell-mediated MHC-I-independent SCLC killing that required BTN2A1.
Contributed by Katherine Turner
ABSTRACT: Small cell lung cancer (SCLC) is a highly aggressive neoplasm with limited sensitivity to anti-PD-(L)1 blockade, which is likely caused by the epigenetic silencing of MHC-I. Elucidating MHC-I-independent immune recognition mechanisms is therefore crucial for enhancing treatment responses and improving clinical outcomes in a greater number of patients. Leveraging single-cell approaches, we discovered γδ T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, γδ T cells maintained a cytotoxic transcriptional profile, suggesting an anti-tumor role. Indeed, high γδ T cell infiltration in two practice-changing clinical trials predicted improved response to anti-PD-L1 immunotherapy in patients with SCLC. Moreover, using preclinical models, we demonstrated that γδ T cells are effective at tarlatamab (delta-like ligand 3 [DLL3]-CD3 bispecific T cell engager [BiTE])-redirected SCLC killing and that zoledronate, an FDA-approved compound, can sensitize SCLC cells to γδ T cell-mediated killing. Thus, our findings suggest that engaged γδ T cells are potentially valuable targets for SCLC therapy.
Author Info:
(1) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The Univers
ity of Melbourne, Parkville, VIC 3010, Australia. Electronic address: ng.ji@wehi.edu.au. (2) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (3) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (4) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. (5) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. (6) Collaborative Centre for Genomic Cancer Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia. (7) Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Pathology, Faculty of Medicine and University of Hospital Cologne, University of Cologne, 50931 Cologne, Germany. (8) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (9) Clinical Translation, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Medicine, Adelaide University, Adelaide, SA 5000, Australia; Department of Clinical Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden; Centre for Health Services Research, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (10) Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA. (11) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (12) Centre for Inflammation Biology and Cancer Immunology, King's College London, London SE1 9RT, UK; Department of Medical Oncology, Guy's Hospital, London SE1 9RT, UK. (13) Collaborative Centre for Genomic Cancer Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) WEHI Advanced Genomics Facility and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (15) WEHI Advanced Genomics Facility and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (16) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (17) WEHI Advanced Genomics Facility and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (18) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (19) Department of Respiratory Medicine, Austin Health, Heidelberg, VIC 3084, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia. (20) Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine and University Hospital Cologne, University Hospital of Cologne, 50931 Cologne, Germany. (21) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (22) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (23) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (24) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (25) Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Respiratory and Sleep Medicine, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia. (26) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: sutherland.k@wehi.edu.au.
