My group works on different aspects of tumor immunology in malignant melanoma with a special emphasis on translational research. Melanoma is a highly mutated and immunogenic malignancy that can be treated with both immunotherapy and targeted agents. However, a substantial number of patients with metastatic disease has no, minimal or short-lived benefit from these therapeutics.
In my group, we are trying to understand which patients are most likely to benefit from immunotherapy. In particular, we want to understand which antigens on cancer cells can be detected by human T cells. So-called (mutated) neoantigens seem to play a major role in this perspective. These tumor antigens are formed by somatic mutations and thereby are private. Recently, we identified another class of neoantigens. These antigens (TURCs) are tumor-specific, recurrent and of cryptic origin since they cannot be attributed to known proteins. We were able to show that TURCs are much more frequent than mutated neoantigens. Currently, we are trying to validate TURCs as T cell antigens and to understand the mechanisms of their formation. Our long-term goal is to develop personalized immunotherapies based on our findings.
Targeted therapy of advanced melanoma is already personalized. In patients with BRAFV600 (~50% of all melanomas), dual MAPK inhibition can prolong survival. However, the majority tumors eventually become resistant and progress. To overcome resistance, combination of targeted therapies and immunotherapy has been proposed. To this end, we are exploring the immunological aspects and consequences of targeted therapy in melanoma patients and how oncogenes modulate the interaction of malignant cells with the immune system. We were able to show that different targeted drugs used against BRAFV600 mutant melanoma have a specific impact on the human immune system. Currently, we are investigating how myeloid cells influence the efficacy of MAPK inhibition in melanoma. Ultimately, we want to understand how to combine or sequence targeted therapy and immunotherapy for maximal patient benefit.
Most important publications
Gangaev A, Rozeman EA, Rohaan MW, Isaeva OI, Philips D, Patiwael S, van den Berg JH, Ribas A, Schadendorf D, Schilling B, Schumacher TN, Blank CU, Haanen JBAG, Kvistborg P. (2021) “Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response” Proc Natl Acad Sci U S A. 2021 Oct 26;118(43):e2102849118.
Glutsch V, Kneitz H, Gesierich A, Goebeler M, Haferkamp S, Becker JC, Ugurel S, Schilling B. (2021) “Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma.” Cancer Immunol Immunother. 2021;70(7):2087-93.
Erhard F, Dölken L, Schilling B, Schlosser A. (2020) “Identification of the Cryptic HLA-I Immunopeptidome.” Cancer Immunol Res. 2020 Aug;8(8):1018-1026.
Conway JR, Dietlein F, Taylor-Weiner A, AlDubayan S, Vokes N, Keenan T, Reardon B, Margolis CA, Weirather J, Haq R, Schilling B, Hodi FS, Schadendorf D, Liu D, Van Allen EM. (2020) “Integrated molecular drivers coordinate biological and clinical states in melanoma.” Nat Genet. 2020;52(12):1373-83.
Liu D*, Schilling B*, Liu D, Sucker A, Livingstone E, Zimmer L, Gutzmer R, Satzger I, Loquai C, Grabbe S, Vokes N, Margolis C, He MX, Elmarkaby H, Dietlein F, Tracy A, Gogas H, Goldinger SM, Utikal J, Blank CU, Rauschenberger R, von Bubnoff D, Krackhardt A, Weide B, Haferkamp S, Kiecker F, Garraway L, Regev A, Flaherty K, Paschen A, van Allen EM#, Schadendorf D#. (2019) “Integrative molecular and clinical modeling of clinical outcomes to PD-1 blockade in metastatic melanoma patients” Nat Med., Dec;25(12):1916-1927. *,# contributed equally