In the Böttcher lab, we are interested in understanding how immune responses are shaped in various tissues, with a particular interest in tumors as well as healthy and diseased barrier tissues such as the lung. In order to understand the cellular and molecular mechanisms that determine the generation of effective and dysfunctional immune responses in these complex tissue microenvironments, our lab employs cutting-edge techniques and methodologies to investigate the function of immune cell populations, cellular interactions and cell-cell communication pathways, and immune checkpoints within these. By integrating our findings with computational and systems biology approaches, we aim to identify targets that help the development of novel immunotherapeutic strategies for diseases such as cancer and chronic viral infections.
Current projects in the lab focus on understanding the pathways tumor cells use to inhibit the coordination of immune responses in tumors by intratumoral dendritic cells (DCs), the molecular mechanisms beyond known immune checkpoints that control tumor-specific T cell responses in tumors and tumor-draining lymph nodes and the regulation of natural killer (NK) cell function during cancer metastasis in the lung.
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Understanding mechanisms of cancer immune evasion
Many cancer cells can produce a bioactive lipid with immunosuppressive function, prostaglandin E2 (PGE2), which contributes to cancer immune evasion. We recently identified a key role for PGE2 in limiting the ability of a specialized subset of dendritic cells, so-called type 1 conventional dendritic cells (cDC1s), to orchestrate anti-cancer CD8+ T cell responses within the tumor microenvironment. We uncovered that PGE2 produced in tumors locally reprograms cDC1s to become dysfunctional, which hinders their ability to produce key chemokines and cytokines that regulate migration and function of tumor-infiltrating CD8+ T cells.
Targeting the PGE2 receptors EP2 and EP4 expressed on cDC1s was able to prevent their dysfunction in tumors and restore cDC1-mediated orchestration of anti-cancer CD8+ T cell responses within the tumor microenvironment.
These results reveal PGE2-induced cDC1 dysfunction as an important mechanism underlying ineffective anti-cancer CD8+ T cell responses in tumors and may help the development of cancer therapies aiming to enhance the functionality of cDC1s in tumors to promote effective anti-cancer immunity.
Currently, we are pursuing several lines of investigation to better characterize how the PGE2-EP2/EP4 axis regulates immune responses by cDC1 and other immune cells in the context of cancer and other diseases such as viral infection.
Local coordination of immune responses in tumors
The mechanisms that determine protective versus dysfunctional immune responses in tumors remain poorly understood. In a recent study, we combined multi-parametric high-resolution tumor microscopy with imaging-based deep learning to explore intratumoral features linked to the outcome of anti-cancer immunity.
By this approach, we identified intratumoral cDC1-CD8+ T cell clusters as a feature of protective anti-cancer immunity. These clusters constitute local intratumoral niches in which cDC1 activated so-called stem-like TCF1+CD8+ T cells.
This approach identified spatially-organized formation of cDC1-CD8+ T cell clusters as a distinguishing feature of tumors susceptible to immune control. We uncovered that these clusters constitute local intratumoral niches for the activation of tumor-specific TCF1+ stem-like CD8+ T cells. In addition, we identified a functionally specialized MHCIIhiCCR7neg cDC1 subpopulation residing in these niches that drives TCF1+CD8+ T cell activation and expansion, ultimately promoting cancer immune control.
Overall, these findings reveal an intratumoral phase of anti-cancer T cell responses orchestrated by MHCIIhiCCR7neg cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy. They further suggest that protective anti-cancer T cell responses underlie a high degree of coordination and spatial organization in the tumor microenvironment, which remains an active area of research in the lab.
Understanding subversion of immunosurveillance in metastatic organ niches
Metastatic disease is one of the major causes of death of cancer patients. We have developed high resolution imaging techniques to investigate how cancer cells manage to evade recognition by the immune system during metastasis, with a focus on the colonization of distant organs such as lung and liver by disseminated tumor cells.
Overcoming barriers limiting anti-cancer T cell responses in tumors
We and others recently uncovered an intratumoral phase of anti-cancer immunity that depends on the expansion and effector differentiation of proliferation-competent TCF1+ stem-like CD8+ T cells within tumor tissue.
In ongoing work, we are investigating the molecular mechanisms that control this important process in order to identify molecules beyond known immune checkpoints that may serve as target for new immunotherapies aiming to elicit effective anti-cancer T cell responses.
Selected publications from the J. Böttcher research group
- Bosch M., Kallin N., Donakonda S., Zhang J.D., Wintersteller H., Hegenbarth S., Heim K., Ramirez, C., Fürst A., Lattouf E.I., Feuerherd M., Chattopadhyay S., Kumpesa N., Griesser V., Hoflack J.C., Siebourg-Polster J., Mogler C., Swadling L., Pallett L.J., Meiser P., Manske K., de Almeida, G.P., Kosinska A.D., Sandu I., Schneider S., Steinbacher V., Teng Y., Schnabel J., Theis F., Gehring A.J., Boonstra A., Janssen H., Vandenbosch M., Cuypers E., Öllinger R., ENgleitner T. Rad R., Steiger K., Oxenius A., Lo Wa.L., Klepsch V., Bayer G., Holzmann B., Maini M.K., Heeren R., Murray P.J., Thimme R., Herrmann C., Protzer U., Böttcher J.P., Zehn D., Wohlleber D., Mauer G.M., Hofmann M., Luangsay S. and Knolle P.A. (2024). A PKA-operated liver tissue-rheostat curbs TCR signalling and effector function of virus-specific CD8 T cells in chronic hepatitis B virus infection. Nature. 631, 867–875. https://doi.org/10.1038/s41586-024-07630-7
- Lacher S., Dörr J., de Almeida G.P., Hönninger J., Meiser P., Bayerl F., Hirschberger A., Pedde A.M., Meiser P., Ramsauer L., Rudolph T.J., Spranger N., Morotti M., Jarosch S., Gregors L., Oner A., Gregor L., Lesch S., Michaelides S., Fertig L., Briukhovetska D., Majed L., Stock S., Busch D.H., Buchholz V.R., Knolle P.A., Zehn D., Kobold S. and Böttcher J.P. (2024). PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells. Nature. 629, 417–425.https://doi.org/10.1038/s41586-024-07254-x
- Morotti M., Grimm A.J., Hope H., Arnaud M., Desbuisson M., Rayroux N., Barras D., Masid M., Murgues B., Chap B., Ongaro M., Rota I., Ronet C., Minasyan A., Ouchen K., Mjahed R-B., Benedetti F., Abdellaoui N., Turrini R., Gannon P., Zaman P., Mathevet P., Lelievre L., Crespo I.,Conrad M., Verdeil G., Kandalaft L., Dagher J., Corria-Osorio J., Doucey M-A., Ho P-C., Harari A., Vannini N., Böttcher J.P., Dangaj Laniti D. and Coukos G (2024). PGE2 inhibits TIL expansion by disrupting IL-2 signalling and metabolism. Nature. 629, 426–434.https://doi.org/10.1038/s41586-024-07352-w
- Afzali A., Nirschl L., Sie C., Pfaller M., Ulianov O., Hassler T., Federle C., Petrozziello E., Kalluri S., Chen H.H., Tyystjärvi S., Muschaweckh A., Lammens K., Delbridge C., Büttner A., Steiger K., Seyhan G., Ottersen O.P., Öllinger R., Rad R., Jarosch S., Straub A., Mühlbauer A., Grassmann S., Hemmer B., Böttcher J.P., Wagner I., Kreutzfeldt M., Merkler D., Pardas I., Schmidt-Supprian M., Buchholz V.R., Heink S., Busch D., Klein L. and Korn T. (2024). B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4. Nature. 627, 407–415.https://doi.org/10.1038/s41586-024-07079-8
- Meiser P., Knolle M., Hirschberger A., Gustavo P.A., Lacher S., Bayerl F., Pedde A.M., Flommersfeld S., Hönninger J., Stark L., Stögbauer F., Anton M., Wirth M., Wohlleber D., Steiger K., Buchholz V.R., Wollenberg B., Zielinski C.E., Braren R., Rückert D., Knolle P.A., Kaissis G. and Böttcher J.P. (2023). A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity. Cancer Cell. Online ahead of print. https://doi.org/10.1016/j.ccell.2023.06.008
- Bayerl F., Meiser P., Donakonda S., Hirschberger A., Lacher S., Pedde A.M., Hermann C.D., Knolle M., Rudolph T.J., Grassmann S., Öllinger R., Kirchhammer N., Trefny M., Elewaut A., Anton M., Wohlleber D., Höchst B., Zaremba A., Krüger A., Rad R., Obenauf A.C., Schadendorf D., Zippelius A., Buchholz V.R., Schraml B.U. and Böttcher J.P. (2023). Tumor-derived PGE2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses. Immunity. 1341-2458. e11. https://doi.org/10.1016/j.immuni.2023.05.011
- Bayerl F., Bejarano D.A., Bertacchi G., Doffin A.-C., Gobbini E., Hubert M., Li L., Meiser P., Müller L., Pedde A.-M., Posch W., Schlitzer A., Schmitz M., Schraml B., Uderhardt S., Valladeau-Guilemond J., Wilflingseder D., Zaderer V. and Böttcher J.P. (2023). Guidelines for visualization and analysis of DC in tissues using multiparameter fluorescence microscopy imaging methods. Eur. J. Immunol. 2249923. https://doi.org/10.1002/eji.202249923
- Flommersfeld S.*, Böttcher J.P.*, Ersching J., Flossdorf M., Meiser P., Pachmayr L.O., Leube J., Hensel I., Jarosch S., Zhang Q., Chaudhry M.Z., Andrae I., Schiemann M., Busch D.H., Cicin-Sain L., Sun J.C., Gasteiger G., Victora G.D., Höfer T., Buchholz V.R. and Grassmann S. (2021). Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection. Immunity. 54: 2288-2304.e7. https://doi.org/10.1016/j.immuni.2021.08.002 *Co-first author
- Dudek M., Pfister D., Donakonda S., Filpe P., Schneider A., Laschinger M., Hartmann D., Hüser N., Meiser P., Bayerl F., Inverso D., Wigger J., Sebode M., Öllinger R., Rad R., Hegenbarth S., Anton M., Guillot A., Bowman A., Heide D., Müller F., Ramadori P., Leone V., Garcia-Caceres C., Gruber T., Seifert G., Kabat A.M., Mallm J.-P., Reider S., Effenberger M., Roth S., Billeter A.T., Müller-Stich B., Pearce E.J., Koch-Nolte F., Käser R., Tilg H., Thimme R., Boettler T., Tacke F., Dufour J.F., Haller D., Murray P., Heeren R., Zehn D., Böttcher J.P., Heikenwälder M., and Knolle P.A. (2021). Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature. 592: 444-449. https://doi.org:10.1038/s41586-021-03233-8
- Böttcher, J.P. and Reis e Sousa, C. (2018). The role of type 1 conventional dendritic cells in cancer immunity. Trends in Cancer. 4: 784–792. https://doi.org/10.1016/j.trecan.2018.09.001
- Böttcher, J.P., Bonavita, E., Chakravarty, P., Blees, H., Cabeza-Cabrerizo, M., Sammicheli, S., Rogers, N.C., Sahai, E., Zelenay, S., Reis e Sousa, C. (2018). NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. Cell 172: 1022–1037. https://doi.org/10.1016/j.cell.2018.01.004
- Böttcher J.P., Beyer M., Meissner F., Abdullah Z., Sander J., Höchst B., Eickhoff S., Rieckmann J.C., Russo C., Bauer T., Flecken T., Giesen D., Engel D., Jung S., Busch D.H., Protzer U., Thimme R., Mann M., Kurts C., Schultze J.L., Kastenmüller W. and Knolle P.A. (2015). Functional classification of memory CD8(+) T cells by CX3CR1 expression. Nature Communications 6: 8306. https://doi.org:10.1038/ncomms9306
For a complete list of publications, please see here on Pubmed.
Our research is supported by funding from the German National Science Foundation (DFG), the German Cancer Aid (DKH), the Elite Network of Bavaria, Bavarian State Ministry of Science and a TUM Junior Fellow Fund.