Digitally Quantified CD8+ Cells - The Best Candidate Marker for an Immune Cell Score in NSCLC?

The TNM classification is well established as a state-of-the-art prognostic and treatment-decision-making tool for NSCLC patients. However, incorporation of biological data may hone the TNM system. This paper focuses on choosing and incorporating subsets of tissue infiltrating lymphocyte (TIL), detected by specific immunohistochemistry (IHC) and automatically quantified by open source software, into a TNM-Immune cell score (TNM-I) for NSCLC. We use common markers (CD3, CD4, CD8, CD20 and CD45RO) of tissue infiltrating lymphocytes (TILs) to identify TIL subsets in tissue micro-arrays (TMAs) comprising tumor tissue from 553 patients resected for primary NSCLC. The number of TILs are automatically quantified using open source software (QuPath). Their prognostic efficacy, alone and within a TNM-I model, is evaluated in all patients and histological subgroups. Compared to previous manual semi-quantitative scoring of TILs in the same cohort, the present digital quantification proved superior. As a proof of concept, we construct a TNM-I, using TNM categories and the CD8+ TILs density. The TNM-I is an independent prognosticator of favorable diagnosis in both the overall cohort and in the main histological subgroups. In conclusion, CD8+ TILs density is the most promising candidate marker for a TNM-I in NSCLC. The prognostic efficacy of the CD8+ TILs density is strongest in LUSC, whereas both CD8+ TILs and CD20+ TILs, or a combination of these, may be candidates for a TNM-I in LUAD. Further, based on the presented results, digital quantification is the preferred method for scoring TILs in the future.