Distinct tumor-infiltrating lymphocyte landscapes are associated with clinical outcomes in localized non-small-cell lung cancer

L Federico; D J McGrail; S-E Bentebibel; C Haymaker; A Ravelli; M-A Forget; T Karpinets; P Jiang; A Reuben; M V Negrao; J Li; R Khairullah; J Zhang; A Weissferdt; A A Vaporciyan; M B Antonoff; G Walsh; S-Y Lin; A Futreal; I Wistuba; J Roth; L A Byers; P-O Gaudreau; N Uraoka; A F Cruz; H Dejima; R N Lazcano; L M Solis; E R Parra; J J Lee; S Swisher; T Cascone; J V Heymach; J Zhang; B Sepesi; D L Gibbons; C Bernatchez

doi:10.1016/j.annonc.2021.09.021

Distinct tumor-infiltrating lymphocyte landscapes are associated with clinical outcomes in localized non-small-cell lung cancer

Ann Oncol. 2022 Jan;33(1):42-56. doi: 10.1016/j.annonc.2021.09.021. Epub 2021 Oct 13.

Authors

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 Zhang⁵, 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

Affiliations

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: [email protected].
¹² Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: [email protected].
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: [email protected].
¹⁴ Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: [email protected].

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.

Keywords: T cells; biomarkers; immune system; lung cancer; microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Carcinoma, Non-Small-Cell Lung* / pathology
Humans
Lung Neoplasms* / pathology
Lymphocytes, Tumor-Infiltrating / pathology
Prognosis

Abstract

Publication types

MeSH terms

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