Deciphering Microenvironment of NSCLC based on CD8+ TIL Density and PD-1/PD-L1 Expression

Abstract

Purpose: To determine whether distinct tissue immune microenvironments differentially impact on clinical outcome in non-small cell lung cancer (NSCLC), an extended analysis of PD-1/PD-L1 and Tumor Infiltrating Lymphocytes (TILs) was performed.Materials and Methods: 1016 NSCLC mRNA-sequence samples from The Genome Data Analysis Center (TCGA) and 275 NSCLC mRNA-microarray samples from Gene Expression Omnibus (GEO) were included as testing cohort and validation cohort respectively. Enrichment scores of CD8+ T cells' metagene were used for quantifying its infiltrating density. Based on the median values of CD8+ T cell density and PD-1/PD-L1 mRNA expression, the samples were classified into four Tumor Immune Microenvironment types (TIMTs). Overall survival, as well as clinicopathological features, mutational profiles, mismatch repair score etc. were compared across the four types.Results: Neither PD-1 expression nor PD-L1 expression was associated with outcome in the overall NSCLC. Classification of TIMT based on PD-1/PD-L1 and CD8+ TIL could efficiently classify patients of different survival in ADC but not SCC, with the best overall survival achieved in TIMT3 (high CD8+ TIL and low PD-1/PD-L1), whereas TIMT2 (low CD8+ TIL and high PD-1/PD-L1) manifested the worst outcome. TIMT classification based on PD-1/ CD8+ TIL could better stratify patient of different prognosis than PD-L1/ CD8+ TIL based classification. EGFR wide type and IFNγ overexpression were associated with TIMT4 (high PD-1/PD-L1 and high CD8+ TIL), whereas tumor mutational burden (TMB) manifested no significant difference across four TIMTs.Conclusion: The classification of tumors into four microenvironment subtypes based on PD-1/PD-L1 status and CD8+ TIL is an appropriate approach to stratify patients of different clinical outcome and better guide the practical use of immunotherapy.

Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution

“…Others showed that the extent of immunological infiltration in tumor tissue and the expression of immune checkpoints proved to be a reliable marker for response to anti-PD-1 immunotherapy and long-term survival NSCLC [38], and other malignancies, like breast cancer [39], melanoma [40], colorectal carcinoma [41], and prostatic cancer [42] as well. Another group indicated on NSCLC TMA samples that a high number of stromal CD4 + and epithelial and stromal CD8 + cells were independent positive prognostic markers, and CD8 + tumor-infiltrating lymphocytes (TILs) can stratify immunotherapy-treated patients of different clinical outcome [43]. Furthermore, a low level of CD8 + lymphocyte infiltration in tumor stroma was positively correlated with an augmented incidence of angiolymphatic tumor invasion [38].…”

Histopathological Analysis of Tumor Microenvironment and Angiogenesis in Pheochromocytoma

“…The status of CD8 + TILs has been generally reported to be correlated with better prognosis ( 33 – 35 ). Our results did demonstrate that CD8 + TILs could play pivotal roles in possible biological behavior of PHEOs and its abundance could also represent relatively benign tumors as reported in other human malignancies ( 33 – 35 ). However, it awaits further investigations for clarification.…”

Surprising impact of stromal TIL’s on immunotherapy efficacy in a real-world lung cancer study

“…The critical importance of CD8+T-cells was also shown by Lin et al involving 1016 NSCLC mRNA-sequence samples from The Genome Data Analysis Center (TCGA) and 275 NSCLC mRNA-microarray samples from Gene Expression Omnibus (GEO) as testing and validation cohort, respectively. Lin showed that CD8+T-cell infiltration was associated with improved survival [18]. A separate study by Fumet et al looking again at the mRNA sequencing in 1016 NSCLC TCGA samples and 85 samples of NSCLC patients treated with anti-PD-1 for comparison with OS and PFS, respectively, found that CD8 was associated with both a good PFS and OS, while PD-L1 (RNA) was associated with a poor OS in ICI-untreated patients and with a good PFS and OS in patients treated with anti-PD-1 therapy [19].…”