Center for Molecular Medicine Cologne

Schlößer, Hans A - CAP 12

Tumor-specific endogenous immune response and immune escape in gastrointestinal Cancer

Introduction

Immune checkpoint inhibition (CKI) demonstrated remarkable efficacy in several kinds of cancer, representing a major breakthrough in cancer therapy. These therapies are unique, as the primary target is not the tumor cell itself, but the crosstalk between immune cells and cancer cells in the tumor microenvironment. We described a negative prognostic impact of PD-L1 expression on tumor cells in esophago-gastric adenocarcinoma (GC) and CKI is effective in metastatic disease. Interestingly, efficacy of CKI is often not limited to patients with expression of the relevant protein on tumor cells. Recent publications demonstrate that expression of PD-L1 on tumor-infiltrating lymphocytes and tumor cells are of similar importance for immune escape, which explains treatment response in patients with PD-L1 negative tumors. Despite the promising results of early studies, only a minor fraction of patients responds to CKI. Preexisting endogenous immune responses seem to be crucial for immune checkpoint inhibition. A successful immune recognition depends on a broad spectrum of immune-related tumor cell intrinsic or extrinsic aspects and can so far only be predicted partially by very few markers (e.g. mutational burden, PD-L1 expression). Hence, multidimensional analyses of tumor immunogenicity including the immune infiltrate, private and shared tumor antigens, tumor specific immune response and immune escape are crucial to further improve therapeutic efficacy and translational research for this novel aspect of cancer therapy.
We aim to decipher endogenous tumor-specific immune response with a clear focus on GI Cancer. Detailed analyses of endogenous immune response against private and shared antigens will be performed using genomic and functional analyses in preclinical models, untreated tumor samples and patients receiving immune checkpoint inhibition.

Clinical/medical relevance and sustainability in disease understanding

Our research has immediate translational relevance as endogenous immune response is probably the most relevant factor determining success or failure of emerging immunotherapies. Taken together, our analyses hopefully contribute to an implementation of immunotherapy into treatment algorithms of gastrointestinal cancer, improve translational analyses and support a tailored design of future clinical trials. This could be of similar relevance to cancers of different origins.

  • Datta RR, Schran S, Persa OD, Aguilar C, Thelen M, Lehmann J, García-Marquez MA, Wennhold K, Preugszat E, Zentis P, von Bergwelt-Baildon MS, Quaas A, Bruns CJ, Kurschat C, Mauch C, Löser H, Stippel DL, Schlößer HA. Post-transplant malignancies show reduced T-cell abundance and tertiary lymphoid structures as correlates of impaired cancer immunosurveillance. Clin Cancer Res. 2022 Feb 9:clincanres.3746.2021. doi: 10.1158/1078-0432.CCR-21-3746. Online ahead of print. PMID: 35191474
  • Mellinghoff SC, Thelen M, Bruns C, Garcia-Marquez M, Hartmann P, Lammertz T, Lehmann J, Nowag A, Stemler J, Wennhold K, Cornely OA, von Bergwelt-Baildon MS, Schlößer HA. T-cells of invasive candidiasis patients show patterns of T-cell-exhaustion suggesting checkpoint blockade as treatment option. Journal of Infection 2022 Feb;84(2):237-247.doi: 10.1016/j.jinf.2021.12.009. Epub 2021 Dec 15.
  • Banck JC, Mueller N, Mellinghoff SC, Thelen M, Fraccaroli A, Blumenberg V, Koehler P, Kunz WG, Rudelius M, Schrotzlmair F, Subklewe M, Schlosser HA, Tischer J, Cornely OA, Lindner LH, and von Bergwelt-Baildon M (2021). Immune Checkpoint Blockade for Aspergillosis and Mucormycosis Coinfection. Hemasphere5, e530. doi:10.1097/HS9.0000000000000530.
                                                                                                • Garcia-Marquez MA, Thelen M, Reinke S, Keller D, Wennhold K, Lehmann J, Veldman J, Borchmann S, Rosenwald A, Sasse S, Diepstra A, Borchmann P, Engert A, Klapper W, von Bergwelt-Baildon M, Brockelmann PJ, and Schlosser HA (2021). Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma. Leukemia. doi:10.1038/s41375-021-01421-z.
                                                                                                • Leuchte K, Staib E, Thelen M, Godel P, Lechner A, Zentis P, Garcia-Marquez M, Waldschmidt D, Datta RR, Wahba R, Wybranski C, Zander T, Quaas A, Drebber U, Stippel DL, Bruns C, von Bergwelt-Baildon M, Wennhold K, and Schlosser HA (2021). Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma. Cancer Immunol Immunother70, 893-907. doi:10.1007/s00262-020-02734-1.
                                                                                                                                                                                                                                                                                                                                                                                • Thelen M, Wennhold K, Lehmann J, Garcia-Marquez M, Klein S, Kochen E, Lohneis P, Lechner A, Wagener-Ryczek S, Plum PS, Velazquez Camacho O, Pfister D, Dorr F, Heldwein M, Hekmat K, Beutner D, Klussmann JP, Thangarajah F, Ratiu D, Malter W, Merkelbach-Bruse S, Bruns CJ, Quaas A, von Bergwelt-Baildon M, and Schlosser HA (2021). Cancer-specific immune evasion and substantial heterogeneity within cancer types provide evidence for personalized immunotherapy. NPJ Precis Oncol5, 52. doi:10.1038/s41698-021-00196-x.
                                                                                                                                                                                                                                                                                                                                                                                                                            • Wennhold K, Thelen M, Lehmann J, Schran S, Preugszat E, Garcia-Marquez M, Lechner A, Shimabukuro-Vornhagen A, Ercanoglu MS, Klein F, Thangarajah F, Eidt S, Loser H, Bruns C, Quaas A, von Bergwelt-Baildon M, and Schlosser HA (2021). CD86(+) Antigen-Presenting B Cells Are Increased in Cancer, Localize in Tertiary Lymphoid Structures, and Induce Specific T-cell Responses. Cancer Immunol Res9, 1098-1108. doi:10.1158/2326-6066.CIR-20-0949.
                                                                                                                                                                                                                                                                                                                                                                                                                            • Gebauer F, Kramer M, Bruns C, Schlosser HA, Thelen M, Lohneis P, Schroder W, Zander T, Alakus H, Buettner R, Loeser H, and Quaas A (2020). Lymphocyte activation gene-3 (LAG3) mRNA and protein expression on tumour infiltrating lymphocytes (TILs) in oesophageal adenocarcinoma. J Cancer Res Clin Oncol 146, 2319-2327. doi:10.1007/s00432-020-03295-7.
                                                                                                                                                                                                                                                                                                                                                                                                                            • Krämer M, Plum PS, Velazquez Camacho O, Folz-Donahue K, Thelen M, Garcia-Marquez I, Wölwer C, Büsker S, Wittig J, Franitza M, Altmüller J, Löser H, Schlößer HA, Büttner R, Schröder W, Bruns CJ, Alakus H, Quaas A, Chon SH, Hillmer AM. Cell type-specific transcriptomics of esophageal adenocarcinoma as a scalable alternative for single cell transcriptomics. Mol Oncol. 2020 Jun;14(6):1170-1184. doi: 10.1002/1878-0261.12680
                                                                                                                                                                                                                                                                                                                                                                                                                            • Reinke S, Bröckelmann PJ, Iaccarino I, Garcia-Marquez M, Borchmann S, Jochims F, Kotrova M, Pal K, Brüggemann M, Hartmann E, Sasse S, Kobe C, Mathas S, Soekler M, Keller U, Bormann M, Zimmermann A, Richter J, Fuchs M, von Tresckow B, Borchmann P, Schlößer HA, von Bergwelt-Baildon M, Rosenwald A, Engert A, Klapper W. Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1. Blood. 2020 Dec 17;136(25):2851-2863. doi: 10.1182/blood.2020008553.
                                                                                                                                                                                                                                                                                                                                                                                                                            • Renner AM, Ilyas S, Schlosser HA, Szymura A, Roitsch S, Wennhold K, and Mathur S (2020). Receptor-Mediated In Vivo Targeting of Breast Cancer Cells with 17alpha-Ethynylestradiol-Conjugated Silica-Coated Gold Nanoparticles. Langmuir : the ACS journal of surfaces and colloids 10.1021/acs.langmuir.0c02820.
                                                                                                                                                                                                                                                                                                                                                                                                                               
                                                                                                                                                                                                                                                                                                                                                                                                                            • Wagener-Ryczek S, Schoemmel M, Kraemer M, Bruns C, Schroeder W, Zander T, Gebauer F, Alakus H, Merkelbach-Bruse S, Buettner R, Loeser H, Thelen M, Schlosser HA, and Quaas A (2020). Immune profile and immunosurveillance in treatment-naive and neoadjuvantly treated esophageal adenocarcinoma. Cancer Immunol Immunother 69, 523-33.
                                                                                                                                                                                                                                                                                                                                                                                                                            • Zhou C, Fan N, Liu F, Fang N, Plum PS, Thieme R, Gockel I, Gromnitza S, Hillmer AM, Chon SH, Schlosser HA, Bruns CJ, and Zhao Y (2020). Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer. Cells9. doi:10.3390/cells9061481.
                                                                                                                                                                                                                                                                                                                                                                                                                            PD Dr. Hans A Schlößer CMMC Cologne
                                                                                                                                                                                                                                                                                                                                                                                                                            PD Dr. Hans A Schlößer

                                                                                                                                                                                                                                                                                                                                                                                                                            Center for Molecular Medicine Cologne | Clinic of General, Visceral, Tumor and Transplantation Surgery | CMMC Research Building

                                                                                                                                                                                                                                                                                                                                                                                                                            CMMC - PI - CAP 12

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                                                                                                                                                                                                                                                                                                                                                                                                                            +49 221 478 4833

                                                                                                                                                                                                                                                                                                                                                                                                                            Center for Molecular Medicine Cologne | Clinic of General, Visceral, Tumor and Transplantation Surgery | CMMC Research Building

                                                                                                                                                                                                                                                                                                                                                                                                                            Robert-Koch-Str. 21

                                                                                                                                                                                                                                                                                                                                                                                                                            50931 Köln

                                                                                                                                                                                                                                                                                                                                                                                                                            https://viszeral-tumorchirurgie.uk-koeln.de/forschung/molekulare-onkologie/tumorimmunologie/

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                                                                                                                                                                                                                                                                                                                                                                                                                            Publications on PubMed

                                                                                                                                                                                                                                                                                                                                                                                                                            Publications - Hans A Schlößer

                                                                                                                                                                                                                                                                                                                                                                                                                            Link to PubMed

                                                                                                                                                                                                                                                                                                                                                                                                                            Group Members

                                                                                                                                                                                                                                                                                                                                                                                                                            Maximilian Becke (Student)
                                                                                                                                                                                                                                                                                                                                                                                                                            Rabi Raj Datta (Associated Clinician)
                                                                                                                                                                                                                                                                                                                                                                                                                            Dr. Maria Garcia-Marquez (PostDoc)
                                                                                                                                                                                                                                                                                                                                                                                                                            Diandra Keller (Student assistant)
                                                                                                                                                                                                                                                                                                                                                                                                                            Jonas Lehmann (PhD student)
                                                                                                                                                                                                                                                                                                                                                                                                                            Christoph Mallmann (MD, Associated Clinician)
                                                                                                                                                                                                                                                                                                                                                                                                                            Alina Manu (Technician)
                                                                                                                                                                                                                                                                                                                                                                                                                            Sibylle Mellinghoff (MD, Associated Clinician)
                                                                                                                                                                                                                                                                                                                                                                                                                            Ella Preugszat (MD student)
                                                                                                                                                                                                                                                                                                                                                                                                                            Simon Schran (MD student)
                                                                                                                                                                                                                                                                                                                                                                                                                            Martin Thelen (PhD student)
                                                                                                                                                                                                                                                                                                                                                                                                                            Pauline Volkmar (Technician)
                                                                                                                                                                                                                                                                                                                                                                                                                            Dr. Kerstin Wennhold (PostDoc)
                                                                                                                                                                                                                                                                                                                                                                                                                            Lea Wolfsfellner (student)
                                                                                                                                                                                                                                                                                                                                                                                                                            Chenghui Zhou (student)