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 (EGA) and CKI has been approved as adjuvant and palliative treatment. Despite the promising results, only a minor fraction of patients responds to CKI monotherapy and mechanisms underlying resistance are poorly understood. Successful recognition of tumor cells by immune cells is crucial for therapeutic efficacy of CKI. This recognition depends on a broad spectrum of immune-related tumor cell intrinsic or extrinsic aspects and can so far only be predicted partially by surrogate markers (e.g. mutational burden). Hence, multidimensional analyses of tumor immunogenicity including the immune infiltrate, private and shared neoantigens, tumor specific immune response and immune escape are crucial to further improve therapeutic efficacy and translational research in this field. One key project of our group focuses on tumor-specific endogenous immune response in EGA. Closely related to this project we perform a clinical trial evaluating addition of CKI to neoadjuvant treatment of EGA. The impact of tumor-specific B cell responses on tumor immunogenicity is our second main interest. Overall, we aim to further understand immune escape as key mechanism of primary and secondary resistance to 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.

Figure 1

  • Datta RR, Schran S, Persa OD, Aguilar C, Thelen M, Lehmann J, Garcia-Marquez MA, Wennhold K, Preugszat E, Zentis P, von Bergwelt-Baildon MS, Quaas A, Bruns CJ, Kurschat C, Mauch C, Loser H, Stippel DL, and Schlosser HA (2022). Post-transplant Malignancies Show Reduced T-cell Abundance and Tertiary Lymphoid Structures as Correlates of Impaired Cancer Immunosurveillance. Clin Cancer Res28, 1712-1723. doi:10.1158/1078-0432.CCR-21-3746.
  • 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 (2022). Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma. Leukemia36, 760-771. doi:10.1038/s41375-021-01421-z.
  • 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.
  • 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.
  • 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.
  • 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.
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

+49 221 478 89612

+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/

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Hans A Schlößer

Link to PubMed

Group Members

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