Schlößer, Hans A - assoc. RG 45 (former CAP 12)

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.

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.

For more information, please check the research website. 

• Garcia-Marquez MA, Thelen M, Bauer E, Maas L, Wennhold K, Lehmann J, Keller D, Nikolic M, George J, Zander T, Schroeder W, Mueller P, Yazbeck A, Bruns CJ, Thomas R, Gathof B, Quaas A, Peifer M, Hillmer AM, von Bergwelt-Baildon M and Schlößer HA. Germline homozygosity and allelic imbalance of HLA-I are common in esophago-gastric adenocarcinoma and impair the repertoire of immunogenic peptides.Journal for Immunotherapy of Cancer 2024, Apr 17;12(4):e007268. doi: 10.1136/jitc-2023-007268.
   
• Thelen M, Keller D, Lehmann J, Wennhold K, Weitz J, Bauer E, Gathof B, Brüggemann M, Kotrova M, Quaas A, Mallmann C, Chon SH, Hillmer AM, Bruns CJ, von Bergwelt-Baildon M, Garcia-Marquez MA and Schlößer HA. Immune responses against shared antigens are common in esophago-gastric cancer and can be enhanced using CD40-activated B cells. Journal for Immunotherapy of Cancer 2022 Dec;10(12):e005200. doi: 10.1136/jitc-2022-005200.
   
• 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, Löser H, Stippel DL and Schlößer HA. Post-transplant malignancies show reduced T-cell abundance and tertiary lymphoid structures as correlates of impaired cancer immunosurveillance. Clinical Cancer Research 2022 Apr 14;28(8):1712-1723. doi: 10.1158/1078-0432.CCR-21-3746.
   
• 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 and 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
   
• Garcia-Marquez M, 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, Bröckelmann PJ, and Schlößer HA. Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma. Leukemia 2022 Mar;36(3):760-771. doi: 10.1038/s41375-021-01421-z.
   
• Wennhold K, Thelen M, Lehmann J, Schran S, Preugszat E, Garcia-Marquez MA, Lechner A, Shimabukuro-Vornhagen A, Ercanoglu MS, Klein F, Thangarajah F, Eidt S, Löser H, Bruns CJ, Quaas A, von Bergwelt-Baildon M, Schlößer HA. CD86+ antigen-presenting B cells are increased in cancer, localize in tertiary lymphoid structures and induce specific T cell responses. Cancer Immunol Research 2021 Sep;9(9):1098-1108. doi: 10.1158/2326-6066.CIR-20-0949.
   
• Thelen M, Wennhold K, Lehmann J, Garcia-Marquez MA, Klein S, … Bruns CJ, Quaas A, von Bergwelt-Baildon MS, and Schlößer HA. Cancer-specific immune evasion and substantial heterogeneity within cancer types provide evidence for personalized immunotherapy. NPJ Precision Oncology 2021 Jun 16;5(1):52. doi: 10.1038/s41698-021-00196-x
   
• Leuchte K, Staib E, Thelen M, Gödel 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, Schlößer HA. Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma. Cancer Immunolology Immunotherapy 2021 Apr;70(4):893-907. doi:10.1007/s00262-020-02734-1
   
• Schlößer HA, Thelen M, Lechner A, Wennhold K, Garcia-Marquez MA, Rothschild SI, Staib E, Zander T, Beutner D, Gathof B, Gilles R, Cukuroglu E, Göke J, Shimabukuro-Vornhagen A, Drebber U, Quaas A, Bruns CJ, Hölscher AH, von Bergwelt-Baildon MS. B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies. OncoImmunology 2018 Nov 2;8(1):e1512458. doi: 10.1080/2162402X.2018.1512458.
   
• Schlößer HA, ThelenM, Dieplinger G, von Bergwelt-Baildon A, Garcia-Marquez MA, Reuter S, Shimabukuro-Vornhagen A, Wennhold K, Haustein N, Buchner D, HeiermannN, Kleinert R, Wahba R, Ditt V, KurschatC, Cingöz T, Becker J, Stippel DL* and von Bergwelt-Baildon M*.  Prospective analyses of circulating B-cell subsets in AB0-compatible and AB0-incompatible kidney transplant recipients. American Journal of Transplantation 2017 Feb;17(2):542-550. doi: 10.1111/ajt.14013.