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Surfactant Expression Defines an Inflamed Subtype of Lung Adenocarcinoma Brain Metastases That Correlates with Prolonged Survival Authors

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Surfactant Expression Defines an Inflamed Subtype of Lung Adenocarcinoma Brain Metastases That Correlates with Prolonged Survival Authors Author Manuscript Published OnlineFirst on January 17, 2020; DOI: 10.1158/1078-0432.CCR-19-2184 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title Surfactant expression defines an inflamed subtype of lung adenocarcinoma brain metastases that correlates with prolonged survival Authors Kolja Pocha1*, Andreas Mock1,2,3,4*, Carmen Rapp1, Steffen Dettling1, Rolf Warta1,4, Christoph Geisenberger1, Christine Jungk1, Leila Martins5, Niels Grabe6, David Reuss7,8, Juergen Debus4,9, Andreas von Deimling4,7,8, Amir Abdollahi4,9, Andreas Unterberg1, Christel Herold-Mende1,4 Affiliations 1 Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany 2 Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany 3 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany 4 German Cancer Consortium (DKTK), Heidelberg, Germany 5 Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany 6 Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, University of Heidelberg, Heidelberg, Germany 7 Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany 8 Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Institute of Pathology, Heidelberg University Hospital, Heidelberg 69120, Germany 9 Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany * equal contribution Running Title Surfactant defines inflammation in brain metastases Correspondence Prof. Dr. Christel Herold-Mende, Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Phone: +49 (0) 6221-5637927; Fax: +49 (0) 6221-5633979; E-mail: [email protected] heidelberg.de Conflict of interest: The authors have declared that no conflict of interest exists. [1] Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 17, 2020; DOI: 10.1158/1078-0432.CCR-19-2184 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Purpose: To provide a better understanding of the interplay between the immune system and brain metastases (BMs) to advance therapeutic options for this life-threatening disease. Experimental Design: Tumor-infiltrating lymphocytes (TILs) were quantified by semi-automated whole slide analysis in BMs from 81 lung adenocarcinomas (LUAD). Multi-color staining enabled phenotyping of TILs (CD3, CD8, and FOXP3) on a single cell resolution. Molecular determinants of the extent of TILs in BMs were analyzed by transcriptomics in a subset of 63 patients. Findings in LUAD BMs were related to published multi-omic primary LUAD TCGA data (n=230) and single-cell RNA-seq (scRNA-seq) data (n=52,698). Results: TIL numbers within tumor islands was an independent prognostic marker in patients with LUAD BMs. Comparative transcriptomics revealed that expression of three surfactant metabolism- related genes (SFTPA1, SFTPB, and NAPSA) was closely associated with TIL numbers. Their expression was not only prognostic in BM but also in primary LUADs. Correlation with scRNA-seq data revealed that brain metastases with high expression of surfactant genes might originate from tumor cells resembling alveolar type 2 cells. Methylome-based estimation of immune cell fractions in primary LUAD confirmed a positive association between lymphocyte infiltration and surfactant expression. Tumors with a high surfactant expression displayed a transcriptomic profile of an inflammatory microenvironment. Conclusion: The expression of surfactant metabolism-related genes (SFTPA1, SFTPB, NAPSA) defines an inflamed subtype of lung adenocarcinoma brain metastases characterized by high abundance of TILs in close vicinity to tumor cells, a prolonged survival and a tumor microenvironment which might be more accessible to immunotherapeutic approaches. Translational Relevance Immunotherapies have become a powerful addition to the established therapies in metastatic non- small cell lung cancer. Given the dismal prognosis of brain metastases in these patients it is essential to identify subsets of patients that have a tumor microenvironment that might be more accessible to immunotherapeutic approaches. We provide evidence that a fraction of LUAD brain metastases is indeed characterized by a higher TIL numbers and in close association with an inflamed microenvironment and high expression of surfactant genes. [2] Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 17, 2020; DOI: 10.1158/1078-0432.CCR-19-2184 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Lung cancer is the most common type of cancer worldwide and the most common cause of cancer- related death (1,2). Lung cancer can histologically be divided into two groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC can be further subdivided into subtypes, the most frequent being adenocarcinoma (2,3). Lung adenocarcinoma (LUAD) also accounts for the largest histological subset of brain metastases (BM) (4). Of note, BM are even more frequent than primary brain tumors (5). Patients with BMs have a poor median overall survival of 7-13 months (6). Treatment is usually multimodal and consists of systemic chemotherapy combined with microsurgery, stereotactic radiosurgery, and/or radiotherapy (7). There is increasing evidence for the role of the host immune system in cancer development, suppression, and recurrence (8). In colorectal cancer for instance, the quantification of TILs has become a valid prognostic marker for patient survival and is believed to be superior to the TNM classification (9). Many studies have since confirmed the prognostic power of immune cell infiltrates in a large number of cancer types. The positive effect of cytotoxic T cells and Th1 T cells on survival has been shown; however, the influence of intratumoral Th2, Th17, and Tregs on survival is less clear (10). In patients with LUAD with high overall T cell counts and high cytotoxic T cell counts, prolonged survival has been observed (11). Regulatory T cells, on the other hand, seem to impair prognosis (12). However, in addition to quantity, the spatial distribution of immune cells and their vicinity to tumor cells in terms of localization within tumor islands or retention in the tumor stroma (13,14) and the differences between primary tumors and subsequent metastases must be taken into account. It has been shown that infiltration with cytotoxic T cells decreases from primary lung cancer to metastases (15,16). Nevertheless, data on the impact of T cell infiltration on survival in BM remain controversial, with some studies suggesting a favorable role for CD3+, CD8+, and CD45R0+ T cells (17) and other studies showing no benefit (18,19). Understanding the interplay between the immune system and cancer cells is becoming even more critical in patients with BMs as checkpoint inhibitor therapies are on the rise for treating LUAD (20). [3] Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 17, 2020; DOI: 10.1158/1078-0432.CCR-19-2184 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Knowledge about the immune microenvironment in primary lung cancer cannot be extrapolated to include BMs, due to specialized resident immune and stromal cells, including microglia and astrocytes (21-23), and physical restriction by the blood-brain barrier (BBB) (24). Genomic alterations between primary lung cancer and BM as well as their connection to the immune system are the subject of ongoing research (25). Other data suggest that the amount of T cell infiltration in BM might be related to different DNA methylation patterns (26). Thus, a thorough examination of BM biology, including similarities and differences to the primary tumor, is needed to enable us to understand the role of the immune system in BM. Our study aims to provide a comprehensive analysis of the LUAD BM microenvironment. We assessed the number of TILs able to enter tumor islands and get into contact with tumor cells and showed a positive effect of overall TIL infiltration, as well as helper and cytotoxic T cell infiltration on patient survival. Moreover, based on comparative transcriptomic analyses, we related the extent of infiltration in BMs with the expression of surfactant pathway-related genes and showed that this was also the case in primary LUAD. Multi-omic analysis suggested a surfactant pathway associated change in the immune microenvironment, that might render LUAD susceptible to immune checkpoint inhibition. MATERIAL AND METHODS Patients BM samples were obtained from 81 patients who underwent surgery between November 2002 and December 2014 at the Department of Neurosurgery at Heidelberg University Hospital, Germany. All patients were diagnosed with LUAD. Histology and a tumor cell content ≥ 60% were
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