Image Analysis–based Assessment of PD-L1 and Tumor-Associated Immune Cells Density Supports Distinct Intratumoral Microenvironment Groups in Non–small Cell Lung Carcinoma Patients

Abstract

Purpose We investigated the correlation between immunohistochemical PD-L1 expression and tumor-associated immune cells (TAICs) density in non–small cell lung carcinoma (NSCLC) and correlated them with clinicopathologic variables. Experimental Design Tumor tissue specimens from 254 stage I–III NSCLCs [146 adenocarcinomas; 108 squamous cell carcinomas (SCCs)] were examined. PD-L1 expression in malignant cells and macrophages and the density of TAICs expressing CD3, CD4, CD8, CD57, granzyme B, CD45RO, PD-1, FOXP3, and CD68 were evaluated using immunohistochemistry and image analysis. Results Malignant cells PD-L1 H-score > 5 was detected in 23% of adenocarcinomas and 31% of SCCs, and no significant differences were detected comparing both histologies; the median H-score in macrophages was significantly higher in SCC than in adenocarcinoma (P < 0.001). In adenocarcinoma, high malignant cells PD-L1 expression and high TAIC density correlated with solid histology, smoking history, and airflow limitation. Multivariate analysis demonstrated that high CD57-positive cell density correlated with better recurrence-free survival (RFS; P = 0.0236; HR, 0.457) and overall survival (OS; P = 0.0261; HR, 0.481) rates for SCC. High CD68-positive cell density in intratumoral compartment correlated with better RFS (P = 0.0436; HR, 0.553) for adenocarcinoma. The combination of low CD4/CD8/C68-positive cell density and PD-L1 H-score >5 in malignant cells identified small subset of adenocarcinomas with worse outcomes (RFS: P = 0.036; HR, 4.299; OS: P = 0.00034; HR, 5.632). Conclusions We detected different PD-L1 expression and TAIC density patterns in NSCLC. Distinct groups of tumor microenvironment correlated with NSCLC clinicopathologic features, including outcome.

Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

“…In this regard, we documented that 36% of SCC samples displayed type III intrinsic induction, while in ADC the proportion of type IV and II was consistently higher (32% and 36%, respectively). Additionally, ADC displayed a lower expression of PD-L1 while, in line with other observations (26), the microenvironment seemed to be more chemoattractive for the overall population of T lymphocytes than in SCC. Accordingly, the clinical outcome of our cohort of surgically resected patients consistently varied between the two histotypes in terms of DFS that was considerably higher in SCC compared with ADC (28 months vs. 13 months, P < 0.001).…”

“…These cells are likely responsible for IFNg secretion, the most powerful PD-L1 stimulating factor (45). Secondly, KRAS mutation was associated with a reduced expression of PD-L1, as previously documented (44), while, at variance with the literature (26,46), EGFR mutation did not statistically impact on this parameter. It has been extensively reported that tumors with a greater mutational load could generate more neoantigens leading to a larger repertoire of tumor-specific T cells (41).…”

“…In addition, other components of the tumor microenvironment, such as tumor-infiltrating lymphocytes (TIL), critically contribute to tumor biology and therapeutic response to ICI (24), suggesting that predictive biomarkers aimed at personalized therapy can be obtained by a coordinated multiparametric definition of the immune contexture (24)(25)(26)(27).…”

Baseline and postoperative C-reactive protein levels predict mortality in operable lung cancer

“…New discoveries on the relationship between immune system and cancer have expanded the prospects of LC patient stratification by immune-markers, related to both tumour and the host's immunological status [4]. On the first side, tumour immune microenvironment (TIM) has proved to play a prognostic role in several solid tumours, including LC [5]. This is particularly true for new targeted therapies that modulate tumour-microenvironment cells, expressing programmed cell death protein 1 (PD-1) and its ligand (PD-L1), thereby achieving a substantial tumour regression and prolonged disease stabilisation also in LC patients [6,7].…”

Advances in Molecular Imaging Strategies in Immune Checkpoint Therapy

“…These changes affect special T-cell populations by inducing tolerance to tumors, cause a high expression of inhibitory receptors and related ligands and suppressing T-cell activation which caused anti-tumor T-cells useless in tumor microenvironments. Thus, tumor cells are not recognized by adaptive immunity or innate immunity systems, and can avoid attack from the host immune system (Topalian et al, 2015;Parra et al, 2016). In an era when personalized medicine is strongly advocated in the field of oncology, the sheer diversity of cellular mutations that occur in different cancers poses a significant challenge to the personalization of cancer treatment.…”