Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer (original) (raw)
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Clinical cancer research : an official journal of the American Association for Cancer Research, 2018
The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially affect clinical outcome in non-small cell lung cancer (NSCLC), an extended analysis of PD-L1 and tumor-infiltrating lymphocytes (TIL) was performed. Samples from resected adenocarcinoma (ADC 42), squamous cell carcinoma (SCC 58), and 26 advanced diseases (13 ADC and 13 SCC) treated with nivolumab were analyzed. PD-L1 expression and the incidence of CD3, CD8, CD4, PD-1, CD57, FOXP3, CD25, and Granzyme B TILs were immunohistochemically assessed. PD-L1 levels inversely correlated with N involvement, although they did not show a statistically significant prognostic value in resected patients. The incidence and phenotype of TILs differed in SCC versus ADC, in which and mutations conditioned a different frequency and tissue localization of lymphocytes. NSCLC resected patients with high CD8 lym...
Annals of Surgical Oncology, 2019
Background. We investigated whether the expression of transforming growth factor-beta-induced protein (TGFBI) and intratumoral immune cells including CD8-and Forkhead box protein P3 (Foxp3)-positive T cells in clinical lung cancer patients could predict the therapeutic response to nivolumab. Methods. Thirty-three patients who were treated with nivolumab were enrolled in this study. Immunohistochemical analyses of TGFBI, PD-L1, CD8, Foxp3, and vimentin expression were conducted. Serum concentrations of TGFBI and transforming growth factor-beta1 (TGF-b1) were determined by enzyme-linked immunosorbent assay (ELISA). Results. Cancer TGFBI was not associated with prognosis and therapeutic response to nivolumab, but cancer stromal TGFBI and intratumoral CD8-positive T cells were associated with them. Therefore, we evaluated cancer stromal TGFBI and intratumoral CD8-positive T cells. The high-TGFBI-expression group had poorer clinical responses than did the low-TGFBI-expression group (p \ 0.0001). The number of times nivolumab was administered in the high-CD8-expression group was significantly higher than that in the low-CD8-expression group (p = 0.0046). The high-CD8-expression group had better clinical responses than did the low-CD8-expression group (p = 0.0013). Interestingly, all patients in the high-TGFBI/low-CD8-expression group had progressive disease (PD). In contrast, all patients in the low-TGFBI/high-CD8-expression group had PR ? SD (partial response ? stable disease) by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Conclusions. The dual evaluation of stromal TGFBI and intratumoral CD8-positive T cells could be a useful predictive marker for nivolumab.
Stromal CD8+ T Cell Density - A Promising Supplement to TNM staging in Non-Small Cell Lung Cancer
Clinical Cancer Research, 2015
Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the TNM classification in colorectal cancer. In non-small cell lung cancer (NSCLC) no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8+ tumor infiltrating lymphocytes (TILs) as the most promising candidate. Hence, we validate the impact of stromal CD8+ TIL density as an immunoscore in NSCLC. Experimental Design: The prognostic impact of stromal CD8+ TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I-IIIA NSCLC patients. The Tromso cohort (n=155) was used as training set and the results was further validated in the cohorts from Bodo (n=169), Oslo (n=295), and Denmark (n=178). Tissue microarrays (TMAs) and clinical routine CD8 staining was used for all cohorts. Results: Stromal CD8+ TILs density was an independent prognostic factor in the total material (n=797) regardless of the endpoint; disease-free survival (P<0.001), disease-specific survival (P<0.001) or overall survival (P<0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8+ TIL density within each pathological stage (pStage). In multivariate analysis, stromal CD8+ TIL density and pStage were independent prognostic variables. Conclusions: Stromal CD8+ TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore. Research.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2018
The understanding of immune checkpoint molecules' co-expression in non-small cell lung carcinoma (NSCLC) is important to potentially design combinatorial immunotherapy approaches. We studied 225 formalin-fixed, paraffin-embedded tumor tissues from stage I-III NSCLCs-142 adenocarcinomas (ADCs) and 83 squamous cell carcinomas (SCCs)-placed in tissue microarrays. Nine immune checkpoint markers were evaluated; 4 (PD-L1, B7-H3, B7-H4, and IDO-1) expressed predominantly in malignant cells (MCs) and 5 (ICOS, VISTA, TIM3, LAG3, and OX40) expressed mostly in stromal tumor-associated inflammatory cells (TAICs). All markers were examined using a quantitative image analysis and correlated with clinicopathological features, TAICs, and molecular characteristics. Using above the median value as positive expression in MCs and high density of TAICs expressing those markers, we identified higher expression of immune checkpoints in SCC than ADC. Common simultaneous expression by MCs was PD-L1 + B7...
Cells
Over the last decade, the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced non-small cell lung cancer (NSCLC) patients. PD-L1 tumor expression, along with tumor mutational burden, is currently being explored as a predictive biomarker for responses to immune checkpoint inhibitors (ICIs). However, lung cancer patients may have insufficient tumor tissue samples and the high bleeding risk often prevents additional biopsies and, as a consequence, immunohistological evaluation of PD-L1 expression. In addition, PD-L1 shows a dynamic expression profile and can be influenced by intratumoral heterogeneity as well as the immune cell infiltrate in the tumor and its microenvironment, influencing the response rate to PD-1/PD-L1 axis ICIs. Therefore, to identify subgroups of patients with advanced NSCLC that will most likely benefit from ICI therapies, molecular character...
Cancers, 2021
Immune checkpoint blockade (ICB) with checkpoint inhibitors has led to significant and durable response in a subset of patients with advanced stage EGFR and ALK wild-type non-small cell lung cancer (NSCLC). This has been consistently shown to be correlated with the unique characteristics of each patient’s tumor immune micro-environment (TIME), including the composition and distribution of the tumor immune cell infiltrate; the expression of various checkpoints by tumor and immune cells, such as PD-L1; and the presence of various cytokines and chemokines. In this review, the classification of various types of TIME that are present in NSCLC and their correlation with response to ICB in NSCLC are discussed. This is conducted with a focus on the characteristics and identifiable biomarkers of different TIME subtypes that may also be used to predict NSCLC’s clinical response to ICB. Finally, treatment strategies to augment response to ICB in NSCLC with unresponsive types of TIME are explored.
OncoImmunology
Non-small cell lung cancer (NSCLC) is the second most prevalent type of cancer. With the current treatment regimens, the mortality rate remains high. Therefore, better therapeutic approaches are necessary. NSCLCs generally possess many genetic mutations and are well infiltrated by T cells (TIL), making TIL therapy an attractive option. Here we show that T cells from treatment naive, stage I-IVa NSCLC tumors can effectively be isolated and expanded, with similar efficiency as from normal lung tissue. Importantly, 76% (13/17) of tested TIL products isolated from NSCLC lesions exhibited clear reactivity against primary tumor digests, with 0.5%-30% of T cells producing the inflammatory cytokine Interferon (IFN)-γ. Both CD4 + and CD8 + T cells displayed tumor reactivity. The cytokine production correlated well with CD137 and CD40L expression. Furthermore, almost half (7/17) of the TIL products contained polyfunctional T cells that produced Tumor Necrosis Factor (TNF)-α and/or IL-2 in addition to IFN-γ, a hallmark of effective immune responses. Tumorreactivity in the TIL products correlated with high percentages of CD103 + CD69 + CD8 + T cell infiltrates in the tumor lesions, with PD-1 hi CD4 + T cells, and with FoxP3 + CD25 + CD4 + regulatory T cell infiltrates, suggesting that the composition of T cell infiltrates may predict the level of tumor reactivity. In conclusion, the effective generation of tumor-reactive and polyfunctional TIL products implies that TIL therapy will be a successful treatment regimen for NSCLC patients.
Tumor infiltrating T cells influence prognosis in stage I–III non-small cell lung cancer
Journal of Thoracic Disease, 2020
Background: T cell infiltration in non-small cell lung cancer (NSCLC) is essential for the immunological response to malignant tissue, especially in the era of immune-checkpoint inhibition. To investigate the prognostic impact of CD4 + T helper cells (T h), CD8 + cytotoxic (T c) and FOXP3 + regulatory T (T reg) cells in NSCLC, we performed this analysis. Methods: By counterstaining of CD4, CD8 and FOXP3 we used immunohistochemistry on tissue microarrays (TMA) to evaluate peritumoral T h cells, T reg cells and T c cells in n=294 NSCLC patients with pTNM stage I-III disease. Results: Strong CD4 + infiltration was associated with higher tumor stages and lymphonodal spread. However, strong CD4 + infiltration yielded improved overall survival (OS) (P=0.014) in adenocarcinoma (ADC) and large cell carcinoma (LCC) but not in squamous cell carcinoma (SCC). A CD4/CD8 ratio <1 was associated with high grade NSCLC tumors (P=0.020). High CD8 + T cell infiltration was an independent prognostic factor for OS (P=0.040) and progression-free survival (PFS) (P=0.012) in the entire study collective. The OS benefit of high CD8 + infiltration was especially prominent in PD-L1 negative NSCLC (P=0.001) but not in PD-L1 positive tissue (P=0.335). Moreover, positive FOXP3 + expression in tumor infiltrating lymphocytes was associated with increased OS (P=0.007) and PFS (P=0.014) in SCC but not in ADC and LCC (all P>0.05). Here, prognostic effects were prominent in PD-L1 positive SCC (P=0.023) but not in PD-L1 negative SCC (P=0.236). Conclusions: High proportion of CD8 + T c cells correlated with improved prognostic outcome in stage I-III NSCLC. T h cells and T reg cells have implications on outcome with respect to tumor histology and biology.
Immune and Inflammatory Cell Composition of Human Lung Cancer Stroma
Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3 +), cytotoxic-T cells (CD8 +), T-helper cells (CD4 +), B cells (CD20 +), macrophages (CD68 +), mast cells (CD117 +), mononuclear cells (CD11c +), plasma cells, activated-T cells (MUM1 +), B cells, myeloid cells (PD1 +) and neutrophilic granulocytes (myeloperoxidase +) compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1 + cells) in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition.