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Cancer Immunol Res. 2019 Jun;7(6):896-909. doi: 10.1158/2326-6066.CIR-18-0713. Epub 2019 May 3.

Function of Human Tumor-Infiltrating Lymphocytes in Early-Stage Non-Small Cell Lung Cancer.

Author information

1
Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. shaunobrien81@gmail.com.
2
Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
3
Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
4
Division of Thoracic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
5
Division of Cardiovascular Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
6
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Abstract

Cancer progression is marked by dysfunctional tumor-infiltrating lymphocytes (TIL) with high inhibitory receptor (IR) expression. Because IR blockade has led to clinical responses in some patients with non-small cell lung cancer (NSCLC), we investigated how IRs influenced CD8+ TIL function from freshly digested early-stage NSCLC tissues using a killing assay and intracellular cytokine staining after in vitro T-cell restimulation. Early-stage lung cancer TIL function was heterogeneous with only about one third of patients showing decrements in cytokine production and lytic function. TIL hypofunction did not correlate with clinical factors, coexisting immune cells (macrophages, neutrophils, or CD4+ T regulatory cells), nor with PD-1, TIGIT, TIM-3, CD39, or CTLA-4 expression. Instead, we found that the presence of the integrin αeβ7 (CD103), characteristic of tissue-resident memory cells (TRM), was positively associated with cytokine production, whereas expression of the transcription factor Eomesodermin (Eomes) was negatively associated with TIL function. These data suggest that the functionality of CD8+ TILs from early-stage NSCLCs may be influenced by competition between an antitumor CD103+ TRM program and an exhaustion program marked by Eomes expression. Understanding the mechanisms of T-cell function in the progression of lung cancer may have clinical implications for immunotherapy.

PMID:
31053597
PMCID:
PMC6548666
[Available on 2020-06-01]
DOI:
10.1158/2326-6066.CIR-18-0713

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