L Federico1, D J McGrail2, S-E Bentebibel3, C Haymaker4, A Ravelli3, M-A Forget3, T Karpinets5, P Jiang6, A Reuben6, M V Negrao6, J Li5, R Khairullah6, J Zhang11, A Weissferdt7, A A Vaporciyan8, M B Antonoff8, G Walsh8, S-Y Lin2, A Futreal5, I Wistuba4, J Roth8, L A Byers6, P-O Gaudreau9, N Uraoka4, A F Cruz4, H Dejima4, R N Lazcano4, L M Solis4, E R Parra4, J J Lee10, S Swisher8, T Cascone6, J V Heymach6, J Zhang11, B Sepesi12, D L Gibbons13, C Bernatchez14. 1. Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, USA. 2. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA. 3. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. 4. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. 5. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA. 6. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. 7. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA. 8. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA. 9. Department of Oncology, Queens' University and the Canadian Cancer Trials Group, Kingston, Canada. 10. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA. 11. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: jzhang20@mdanderson.org. 12. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: bsepesi@mdanderson.org. 13. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: dlgibbon@mdanderson.org. 14. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: cbernatchez@mdanderson.org.
Abstract
BACKGROUND: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. PATIENTS AND METHODS: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. RESULTS: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. CONCLUSIONS: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.
BACKGROUND: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. PATIENTS AND METHODS: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. RESULTS: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. CONCLUSIONS: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.
Authors: Stephanie T Schmidt; Neal Akhave; Ryan E Knightly; Alexandre Reuben; Natalie Vokes; Jianhua Zhang; Jun Li; Junya Fujimoto; Lauren A Byers; Beatriz Sanchez-Espiridion; Lixia Diao; Jing Wang; Lorenzo Federico; Marie-Andree Forget; Daniel J McGrail; Annikka Weissferdt; Shiaw-Yih Lin; Younghee Lee; Erika Suzuki; Jeffrey J Kovacs; Carmen Behrens; Ignacio I Wistuba; Andrew Futreal; Ara Vaporciyan; Boris Sepesi; John V Heymach; Chantale Bernatchez; Cara Haymaker; Tina Cascone; Jianjun Zhang; Christopher A Bristow; Timothy P Heffernan; Marcelo V Negrao; Don L Gibbons Journal: JCO Clin Cancer Inform Date: 2022-07
Authors: Frank Rojas; Edwin Roger Parra; Ignacio Ivan Wistuba; Cara Haymaker; Luisa Maren Solis Soto Journal: Cancers (Basel) Date: 2022-06-02 Impact factor: 6.575
Authors: Eva Oswald; Daniel Bug; Anne Grote; Kanstantsin Lashuk; Nassim Bouteldja; Dorothee Lenhard; Anne Löhr; Anke Behnke; Volker Knauff; Anna Edinger; Kerstin Klingner; Simone Gaedicke; Gabriele Niedermann; Dorit Merhof; Friedrich Feuerhake; Julia Schueler Journal: J Immunother Cancer Date: 2022-04 Impact factor: 12.469
Authors: Jesse J Lipp; Limei Wang; Haitang Yang; Feng Yao; Nathalie Harrer; Stefan Müller; Sabina Berezowska; Patrick Dorn; Thomas M Marti; Ralph A Schmid; Belazs Hegedüs; Abdallah Souabni; Sebastian Carotta; Mark A Pearson; Wolfgang Sommergruber; Greg J Kocher; Sean R R Hall Journal: Oncoimmunology Date: 2022-02-09 Impact factor: 8.110