Audrey Lupo

Orchestration and Prognostic Significance of Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer

Purpose: Clear cell renal cell carcinoma (ccRCC) has shown durable responses to checkpoint blockade therapies. However, important gaps persist in the understanding of its immune microenvironment. This study aims to investigate the expression and prognostic significance of immune checkpoints in primary and metastatic ccRCC, in relation with mature dendritic cells (DC) and T-cell densities. Experimental Design: We investigated the infiltration and the localization of CD8+ T cells and mature DC, and the expression of immune checkpoints (PD-1, LAG-3, PD-L1, and PD-L2) in relation with prognosis, in 135 primary ccRCC tumors and 51 ccRCC lung metastases. RNA expression data for 496 primary ccRCC samples were used as confirmatory cohort. Results: We identify two groups of tumors with extensive CD8+ T-cell infiltrates. One group, characterized by high expression of immune checkpoints in the absence of fully functional mature DC, is associated with increased risk of disease progression. The second group, characterized by low expression of immune checkpoints and localization of mature DC in peritumoral immune aggregates (tertiary lymphoid structures), is associated with good prognosis. Conclusions: The expression of the immune checkpoints and the localization of DC in the tumor microenvironment modulate the clinical impact of CD8+ T cells in ccRCC. Clin Cancer Res; 21(13); 3031–40. ©2015 AACR.

Calreticulin Expression in Human Non–Small Cell Lung Cancers Correlates with Increased Accumulation of Antitumor Immune Cells and Favorable Prognosis

A high density of tumor-infiltrating mature dendritic cells (DC) and CD8(+) T cells correlates with a positive prognosis in a majority of human cancers. The recruitment of activated lymphocytes to the tumor microenvironment, primed to recognize tumor-associated antigens, can occur in response to immunogenic cell death (ICD) of tumor cells. ICD is characterized by the preapoptotic translocation of calreticulin (CRT) from the endoplasmic reticulum (ER) to the cell surface as a result of an ER stress response accompanied by the phosphorylation of eukaryotic initiation factor 2α (eIF2α). We conducted a retrospective study on two independent cohorts of patients with non-small cell lung cancer (NSCLC) to investigate the prognostic potential of CRT. We report that the level of CRT expression on tumor cells, which correlated with eIF2α phosphorylation, positively influenced the clinical outcome of NSCLC. High CRT expression on tumor cells was associated with a higher density of infiltrating mature DC and effector memory T-cell subsets, suggesting that CRT triggers the activation of adaptive immune responses in the tumor microenvironment. Accordingly, patients with elevated CRT expression and dense intratumoral infiltration by DC or CD8(+) T lymphocytes had the best prognosis. We conclude that CRT expression constitutes a new powerful prognostic biomarker that reflects enhanced local antitumor immune responses in the lung. Cancer Res; 76(7); 1746-56. ©2016 AACR.

Subsolid Lung Nodule Classification: A CT Criterion for Improving Interobserver Agreement

Purpose To evaluate an objective computed tomographic (CT) criterion for distinguishing between part-solid (PS) and nonsolid (NS) lung nodules. Materials and Methods This study received institutional review board approval, and patients gave informed consent. Preoperative CT studies in all patients who underwent surgery for subsolid nodules between 2008 and 2015 were first reviewed by two senior radiologists, who subjectively classified the nodules as PS or NS. A second reading performed 1 month later used predefined classification criteria and involved a third senior radiologist as well as three junior radiologists. Subsolid nodules were classified as PS if a solid portion was detectable in the mediastinal window setting (nonmeasurable, < 50%, or > 50% of the entire nodule) and were otherwise classified as NS (subclassified as pure or heterogeneous). Interreader agreement was assessed with κ statistics and the intraclass correlation coefficient (ICC). Results A total of 99 nodules measuring a median of 20 mm (range, 5-47 mm) in lung window CT images were analyzed. Senior radiologist agreement on the PS/NS distinction increased from moderate (κ = 0.54; 95% confidence interval [CI]: 0.37, 0.71) to excellent (κ = 0.89; 95% CI: 0.80, 0.98) between the first and second readings. At the second readings, agreement among senior and junior radiologists was excellent for PS/NS distinction (ICC = 0.87; 95% CI: 0.83, 0.90) and for subcategorization (ICC = 0.82; 95% CI: 0.77, 0.87). When a solid portion was measurable in the mediastinal window, the specificity for adenocarcinoma invasiveness ranged from 86% to 96%. Conclusion Detection of a solid portion in the mediastinal window setting allows subsolid nodules to be classified as PS with excellent interreader agreement. If the solid portion is measurable, the specificity for adenocarcinoma invasiveness is high.

Correlation between radiological and pathological features of operated ground glass nodules.

Abstract The aim of this study was to evaluate, in a predominantly white population, correlations between radiological and pathological diagnoses based on the latest classifications of pulmonary adenocarcinomas. We analysed data from patients undergoing lung resection for ground glass nodules (GGNs) less than 3 cm and whose solid component was

Immune contexture and histological response after neoadjuvant chemotherapy predict clinical outcome of lung cancer patients

ABSTRACT There is now growing evidence that the immune contexture influences cancer progression and clinical outcome of patients with non-small cell lung cancer (NSCLC). If chemotherapy is widely used to treat patients with advanced-stage NSCLC, it remains unclear how it could modify the immune contexture and impact its prognostic value. Here, we analyzed two retrospective cohorts, respectively composed of 122 stage III-N2 NSCLC patients treated with chemotherapy before surgery and 39 stage-matched patients treated by surgery only. In patients treated with neoadjuvant chemotherapy, the histological characteristics, the expression of PD-L1 protein, and the tumor immune microenvironment (CD8+ T cells, DC-LAMP+ mature dendritic cells, and CD68+ macrophages) were evaluated and their prognostic value assessed together with standard clinical parameters. By analyzing pre- and post-treatment specimens, we did not find any changes in the PD-L1 expression. We also found that the tumor immune contexture in patients treated with neoadjuvant chemotherapy exhibited a similar pattern that the one found in chemotherapy-naive patients, with comparable densities of tumor-infiltrating CD8+ and DC-LAMP+ cells and a similar spatial organization. The percentage of residual viable tumor cells and the immune pattern (CD8+ and DC-LAMP+ cell densities) were significantly associated with the clinical outcome and allowed the identification of short- and long-term survivors, respectively. In multivariate analysis, the immune pattern was found to be the strongest independent prognostic factor. In conclusion, this study decrypts the complex interplay between cancer and immune cells in patients undergoing chemotherapy and supports potential beneficial synergistic effect of immunotherapy and chemotherapy.