Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma

Kinoshita, Tomonari; Kudo-Saito, Chie; Muramatsu, Reiko; Fujita, Toshio; Saito, Masafumi; Nagumo, Haruna; Sakurai, Toshiharu; Noji, Shinobu; Takahata, E.; Yaguchi, Tomonori; Tsukamoto, Nobuo; Hayashi, Yuichiro; Kaseda, Kaoru; Kamiyama, Ikuo; Ohtsuka, Takashi; Tomizawa, Kenji; Shimoji, Masaki; Mitsudomi, Tetsuya; Asamura, Hisao; Kawakami, Yutaka

doi:10.1016/j.ejca.2017.08.026

Cited by 66 publications

(56 citation statements)

References 30 publications

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“…Despite these limitations, the present study demonstrates an initial glimpse into comprehensive leukocyte profiling present in the TiME of PTC and yield three previously unreported findings: first, the TiME of PTC is myeloid inflamed relative to adjacent nonmalignant tissue; second, tumors with a more myeloid hypo‐inflamed TiME phenotype were more likely to demonstrate aggressive pathological features as compared to PTCs with a more lymphoid‐dominant TiME; and third, while BRAF V600E mutant PTCs were not consistently more pathologically aggressive, they did demonstrate increased mast cell infiltration and decreased CD8 + T cell:T REG ratios, indicating that BRAF mutations may contribute to the relatively “immunosuppressed” TiME phenotype. Overall, these findings support the hypothesis that tumor‐immune interactions in PTC reflect an important factor in disease pathogenesis and outcomes, and are consistent with recent reports in colon carcinoma, head and neck squamous cell carcinoma, non‐small cell lung carcinoma, urothelial carcinoma, and other malignancies, where presence, location, and functional status of CD8 + T cells correlates with disease outcome. Although myeloid cell phenotype and presence was not considered in these other studies, as myeloid‐targeted immune therapeutics enter the clinical arena, it is clear that deep characterization and understanding of both arms of the immune system must be considered for efficient and improved patient stratification, as well as for relieving T cell‐suppressive mechanisms ascribed to various myeloid cell and B cell subsets common to TiMEs in solid tumors, including PTC.…”

Section: Discussionsupporting

confidence: 90%

Tumor immune microenvironment characteristics of papillary thyroid carcinoma are associated with histopathological aggressiveness and BRAF mutation status

et al. 2019

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Background Papillary thyroid carcinoma (PTC) follows an indolent course; however, up to 30% of patients develop recurrent disease requiring further treatment. Profiling PTC immune complexity may provide new biomarkers for improved risk prediction. Methods Immune complexity profiles were quantitatively evaluated by multiplex immunohistochemistry (mIHC) in archived tissue sections from 39 patients with PTC, and were assessed for correlations with aggressive histopathological features based on the presence of lymphovascular invasion and/or extrathyroidal extension, and BRAF V600E mutational status. Results mIHC revealed two distinct immune clusters stratifying patients: a lymphoid‐inflamed group (higher CD8+ T cells, reduced dendritic and mast cells) and a myeloid/hypo‐inflamed group that correlated with aggressive pathological features. BRAF mutation was not associated with aggressive pathological features but did correlate with increased mast cell density. Conclusions Distinct immune microenvironments exist in PTC correlating with pathological aggressiveness. Immune‐based biomarkers associated with possible tumor‐immune interactions may be used for risk stratification.

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Section: Discussionsupporting

confidence: 90%

Tumor immune microenvironment characteristics of papillary thyroid carcinoma are associated with histopathological aggressiveness and BRAF mutation status

et al. 2019

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“…Increased TILs have been reported to be a favorable prognostic factor in NSCLC . However, CD8 + T cells have been associated with a better or a worse prognosis in NSCLC. It may be due to different histological subtypes of NSCLC and whether CD8 + T cells are sufficiently activated.…”

Section: Discussionmentioning

confidence: 99%

The landscape of immune microenvironment in lung adenocarcinoma and squamous cell carcinoma based on PD‐L1 expression and tumor‐infiltrating lymphocytes

et al. 2019

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Aims The aim of this study was to investigate the tumor microenvironment immune types (TMIT) based on tumor cell programmed cell death ligand 1 (PD‐L1) expression and tumor‐infiltrating lymphocytes (TILs) distribution and whether distinct TMIT subtypes (TMIT I, PD‐L1high/TILhigh; TMIT II, PD‐L1low/TILlow; TMIT III, PD‐L1high/TILlow; and TMIT IV, PD‐L1low/TILhigh) differentially affect clinical outcomes of patients with lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). Methods and results Immunohistochemistry (IHC) was applied to evaluate the expression of PD‐L1 and the spatial distribution of programmed cell death 1 (PD‐1) and CD8 TILs on the surgically resected specimens from 205 cases of LAC and 149 cases of SCC. PD‐1 and CD8 TILs were more frequently distributed in SCC than those in LAC, regardless of their infiltrating in the tumor islets or stroma. The density of TILs was a poor prognostic factor in LAC but a favorable one in SCC. PD‐L1 levels and its clinical prognostic significance differed in LAC vs SCC. LAC patients with TMIT III and SCC patients with TMIT I had the longest survival, respectively (P = .0197 and .0049). Moreover, TMIT stratification based on tumor cell PD‐L1 expression and stromal CD8+ TILs could be considered as an independent prognostic factor of SCC patients' survival as determined by both univariate and multivariate analysis. Conclusion Our study indicates that different type of TMIT provides its specific microenvironment with diverse impact on survival of LAC and SCC patients and highlights the importance of the integrative assessment of PD‐L1 status and TILs' spatial distribution to predict patients' prognosis.

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“…In non‐small cell lung cancer (NSCLC), immunotherapy has shown promising results and tumour‐infiltrating T cells play a critical role in this process, particularly CD8+ T cells . In addition, the density of different intratumoural immune cells (eg, dendritic cells, macrophages, and CD8+ T cells) has been shown to correlate with various clinicopathological factors including smoking status, pathological stage and different molecular alterations . Furthermore, there is an increasing awareness that traditional tumour‐node‐metastasis (TNM) staging provides incomplete prognostication, and that molecular findings and characterisation of the TME can provide an enhanced ability to predict outcomes in NSCLC patients, particularly those that may be in the same TNM staging group .…”

Section: Introductionmentioning

confidence: 99%

Quantitative image analysis for CD8 score in lung small biopsies and cytology cell‐blocks

et al. 2020

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Introduction Immunotherapy has shown promising results in non‐small cell lung cancer (NSCLC), for which tumour‐infiltrating cytotoxic (CD8+) T cells play a critical role. We investigated the utility of image analysis (IA) to quantify CD8+ T cells in a series of matched small biopsies and resections of NSCLC. Methods CD8 immunohistochemistry was performed on cell‐blocks (CB), core needle biopsies (CNB) and corresponding resections from primary NSCLCs. Slides were digitised using an Aperio AT2 scanner (Leica) and annotated by whole slide image (WSI) or fields of view occupied by tissue spots (TS). Quantitative IA was performed with a customised Aperio algorithm (Leica). CD8 scores (number of T cells with 1‐3+ staining/total area) were then compared. Results Forty‐four cases with CB or CNB material and a corresponding resection were analysed. Average CD8 score was determined in CB (7.67 WSI, 77.67 TS) and/or CNB (47.35 WSI, 325.67 TS), and corresponding resections (190.35 WSI, 336.58 TS). CD8 score concordance was highest (78.6%) for CNBs using WSI annotation. Overall, small biopsies (CB or CNB) correlated with the resection in 71.4% cases using WSI and 63.3% cases using TS annotation. IA performed better for low CD8 scores. Conclusions These findings show that CD8 density in NSCLC can be quantified by IA in small biopsies and cell blocks, achieving the best concordance using WSI scores. Discrepancies were attributed to values near the cut‐off and background detection of staining. These data warrant future studies with more cases and follow‐up data to further investigate the clinical utility of IA for CD8 analysis in NSCLC.

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Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma

Cited by 66 publications

References 30 publications

Tumor immune microenvironment characteristics of papillary thyroid carcinoma are associated with histopathological aggressiveness and BRAF mutation status

Tumor immune microenvironment characteristics of papillary thyroid carcinoma are associated with histopathological aggressiveness and BRAF mutation status

The landscape of immune microenvironment in lung adenocarcinoma and squamous cell carcinoma based on PD‐L1 expression and tumor‐infiltrating lymphocytes

Quantitative image analysis for CD8 score in lung small biopsies and cytology cell‐blocks

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