inhibitory T cell receptor; T cell exhaustion; Cancer; T cells; transcriptional profiling; immunotherapy
Trefny Marcel P., Rothschild Sacha I., Uhlenbrock Franziska, Rieder Dietmar, Kasenda Benjamin, Stanczak Michal A., Berner Fiamma, Kashyap Abhishek S., Kaiser Monika, Herzig Petra, Poechtrager Severin, Thommen Daniela S., Geier Florian, Savic Spasenija, Jermann Philip, Alborelli Ilaria, Schaub Stefan, Stenner Frank, Früh Martin, Trajanoski Zlatko, Flatz Lukas, Mertz Kirsten D., Zippelius Alfred, Läubli Heinz (2019), A Variant of a Killer Cell Immunoglobulin-like Receptor Is Associated with Resistance to PD-1 Blockade in Lung Cancer, in Clinical Cancer Research
, 25(10), 3026-3034.
Läubli Heinz, Balmelli Catharina, Kaufmann Lukas, Stanczak Michal, Syedbasha Mohammedyaseen, Vogt Dominik, Hertig Astrid, Müller Beat, Gautschi Oliver, Stenner Frank, Zippelius Alfred, Egli Adrian, Rothschild Sacha I. (2018), Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events, in Journal for ImmunoTherapy of Cancer
, 6(1), 40-40.
Thommen Daniela S., Koelzer Viktor H., Herzig Petra, Roller Andreas, Trefny Marcel, Dimeloe Sarah, Kiialainen Anna, Hanhart Jonathan, Schill Catherine, Hess Christoph, Savic Prince Spasenija, Wiese Mark, Lardinois Didier, Ho Ping-Chih, Klein Christian, Karanikas Vaios, Mertz Kirsten D., Schumacher Ton N., Zippelius Alfred (2018), A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade, in Nature Medicine
, 24(7), 994-1004.
Läubli Heinz, Koelzer Viktor H., Matter Matthias S., Herzig Petra, Dolder Schlienger Béatrice, Wiese Mark Nikolaj, Lardinois Didier, Mertz Kirsten D., Zippelius Alfred (2017), The T cell repertoire in tumors overlaps with pulmonary inflammatory lesions in patients treated with checkpoint inhibitors, in OncoImmunology
, 7(2), e1386362-e1386362.
T cell dysfunction is increasingly recognized as an important target in cancer immunotherapy highlighted by the successful introduction of antibodies targeting inhibitory T cell receptors, such as PD-1, into the clinical setting. In this proposal, we aim at characterizing the spectrum of inhibitory signals in tumor lesions, obtained from patients with non-small cell lung cancer and epithelial ovarian cancer, to gain a broader view of inhibitory signatures, which may predict T cell dysfunction. First, we will determine the diversity and expression pattern of inhibitory receptors present on tumor-infiltrating T cells, perform a comparative analysis with T cell function and define differentially activated molecular pathways in tumor-infiltrating T cells with distinct stages of T cell activation. To illuminate the mechanisms governing T cell responsiveness, we will use multiparameter flow cytometry, T cell functional assays as well as high-throughput RNA sequencing and quantitative gene expression analysis. In a second step, we aim at developing strategies to overcome tumor-induced T cell dysfunction. To this end, we will assess the T cell stimulatory capacity of a novel (EpCAM x CD3) T cell bispecific antibody (TCB) in human tumor specimens to obtain mechanistic insights into T cell activation. To fully recover T cell function, we will use antibodies, which are capable to antagonize distinct inhibitory receptors on T cells, such as PD-1 and Tim-3. Finally, we will assess molecular and cellular mechanisms that undermine the activity of the (EpCAM x CD3) TCB in human tumors. This will allow us to dissect molecular and transcriptional events that predict and regulate resistance towards therapy with TCBs. A comprehensive view on mechanisms underlying T cell dysfunction will provide the rationale basis for optimizing T cell based therapies with the aim of complete T cell recovery, thereby unleashing the full armamentarium of effector functions in tumor-infiltrating T cells.