Journal
LUNG CANCER
Volume 117, Issue -, Pages 73-79Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.lungcan.2018.01.022
Keywords
Non-small cell lung cancer; Intratumoral T cells; Immune cells; Spatial distances; T regulatory cells; Spatial computation
Categories
Funding
- Lung Cancer Priority Program at MD Anderson Cancer Center
- Mabuchi Research Fund
- CCSG Bioinformatics Shared Resource [P30 CA016672]
- Institutional Research Grant from The University of Texas MD Anderson Cancer Center (MD Anderson) [CPRIT RP170719]
- Career Development Award from the MD Anderson Brain Tumor SPORE
- American Cancer Society [RSG-16-005-01]
- NATIONAL CANCER INSTITUTE [P30CA016672, R37CA214955] Funding Source: NIH RePORTER
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Objectives: To determine the prognostic significance of spatial proximity of lung cancer cells and specific immune cells in the tumor microenvironment. Materials and methods: We probed formalin-fixed, paraffin-embedded (FFPE) tissue microarrays using a novel tyramide signal amplification multiplexing technique labelling CD8, CD4, Foxp3, and CD68+ cells. Each multiplex stained immunohistochemistry slide was digitally processed by Vectra INFORMS software, and an X-and Y-coordinate assigned to each labeled cell type. The abundance and spatial location of each cell type and their proximity to one another was analyzed using a novel application of the G-cross spatial distance distribution method which computes the probability of finding at least one immune cell of any given type within a rpm radius of a tumor cell. Cox proportional hazards multiple regression was used for multivariate analysis of the influence of proximity of lymphocyte types. Results: Pathologic tumor specimens from 120 NSCLC patients with pathologic tumor stage I III disease were analyzed. On univariate analysis, age (P = .0007) and number of positive nodes (P = .0014) were associated with overall survival. Greater area under the curve (AUC) of the G-cross function for tumor cell-Treg interactions was significantly associated with worse survival adjusting for age and number of positive nodes (HR 1.52 (1.11-2.07), P = .009). Greater G-cross AUC for T-reg-CD8 was significantly associated with better survival adjusting for age and number of positive lymph nodes (HR 0.96 (0.92-0.99), P = .042). Conclusion: Increased infiltration of regulatory T cells into core tumor regions is an independent predictor of worse overall survival in NSCLC. However, increased infiltration of CD8 + cytotoxic T cells among regulatory T cells seems to mitigate this effect and was significantly associated with better survival. Validation of the G-cross method of measuring spatial proximity between tumor and immune cell types and exploration of its use as a prognostic factor in lung cancer treatment is warranted.
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