EPFL BioE Talks SERIES "A Novel Role of IL-10 in Preventing T-Cell Exhaustion and Maintaining Anti-tumor Immunity"
Event details
| Date | 31.10.2022 |
| Hour | 16:00 › 17:00 |
| Speaker | Martina Seiffert, Ph.D., Group leader – Immune Modulation in Cancer, German Cancer Research Center (DKFZ), Heidelberg (DE) |
| Location | Online |
| Category | Conferences - Seminars |
| Event Language | English |
WEEKLY EPFL BIOE TALKS SERIES
Abstract:
Chronic antigenic stimulation in tumors drives T-cells into terminal differentiation or “exhaustion”, a cell state that is characterized by the expression of inhibitory receptors like PD-1, and the loss of proliferative and functional properties. We explored microenvironmental signals regulating this process. Using single-cell analyses, we identified a subset of CD8+ effector T-cells with high (hi) PD-1 expression and exhausted phenotype that accumulated in secondary lymphoid organs of mouse models and patients with chronic lymphocytic leukemia (CLL) during disease progression. These T-cells were transcriptionally distinct from less differentiated cells with intermediate (int) PD-1 expression which showed a higher functional competence. The balance between these two CD8+ T-cell subtypes was regulated by interleukin-10 (IL-10) receptor signaling. Genetic depletion or blocking of IL-10 receptor signaling resulted in a dramatic loss of the PD-1(int) subset and an accumulation of activated but dysfunctional PD-1(hi) cells, leading to a significantly enhanced tumor development. Mechanistically, IL-10 receptor blockade altered chromatin accessibility and disrupted the cooperativity of the transcription factors NFAT and AP-1 in CD8+ T-cells. Analyses of clinical data revealed that low IL-10 expression or loss of IL-10 receptor signaling correlated with poor survival and enhanced CD8+ T-cell exhaustion in cancer patients. Thus, IL-10 receptor signaling prevents activation-induced exhaustion of tumor-reactive CD8+ T-cells, which could be exploited for improving immunotherapy.
Bio:
Martina Seiffert is heading the group «Immune Modulation in Cancer» within the Division of Molecular Genetics at the German Cancer Research Center (DKFZ) in Heidelberg, Germany. She is interested in immune modulatory mechanisms in the tumor microenvironment, with a focus on B-cell lymphoma and brain metastases.
Using innovative single-cell omics approaches, her team analyses the immune and stromal compartment of tumors to decipher tumor-supportive and immunosuppressive mechanisms and to suggest novel immunotherapy targets. The lab has established various coculture models of primary patient samples, as well as mouse models, that are used for studying disease biology as well as for pre-clinical testing of drugs. They recently identified the L-amino acid oxidase IL4I1 as a novel metabolic immune checkpoint that contributes to immune escape in cancer. The group has further demonstrated a novel role of IL-10 in preventing T-cell exhaustion and maintaining anti-tumor immunity.
After studying biology at the University of Constance, Germany and the University of Oregon, Eugene, USA, Dr. Seiffert obtained her PhD at the University of Tübingen, Germany, investigating the bone marrow microenvironment in hematopoietic malignancies. As a postdoctoral fellow, she continued her research at the University of Tübingen and the Fred Hutchinson Cancer Research Center in Seattle, USA, focusing on oncogenic signaling in malignant and stromal cells in cancer.
Zoom link (with one-time registration for the whole series) for attending remotely: https://go.epfl.ch/EPFLBioETalks
Instructions for 1st-year Ph.D. students who are under EDBB’s mandatory seminar attendance rule:
IF you are not attending in-person in the room, please make sure to
Abstract:
Chronic antigenic stimulation in tumors drives T-cells into terminal differentiation or “exhaustion”, a cell state that is characterized by the expression of inhibitory receptors like PD-1, and the loss of proliferative and functional properties. We explored microenvironmental signals regulating this process. Using single-cell analyses, we identified a subset of CD8+ effector T-cells with high (hi) PD-1 expression and exhausted phenotype that accumulated in secondary lymphoid organs of mouse models and patients with chronic lymphocytic leukemia (CLL) during disease progression. These T-cells were transcriptionally distinct from less differentiated cells with intermediate (int) PD-1 expression which showed a higher functional competence. The balance between these two CD8+ T-cell subtypes was regulated by interleukin-10 (IL-10) receptor signaling. Genetic depletion or blocking of IL-10 receptor signaling resulted in a dramatic loss of the PD-1(int) subset and an accumulation of activated but dysfunctional PD-1(hi) cells, leading to a significantly enhanced tumor development. Mechanistically, IL-10 receptor blockade altered chromatin accessibility and disrupted the cooperativity of the transcription factors NFAT and AP-1 in CD8+ T-cells. Analyses of clinical data revealed that low IL-10 expression or loss of IL-10 receptor signaling correlated with poor survival and enhanced CD8+ T-cell exhaustion in cancer patients. Thus, IL-10 receptor signaling prevents activation-induced exhaustion of tumor-reactive CD8+ T-cells, which could be exploited for improving immunotherapy.
Bio:
Martina Seiffert is heading the group «Immune Modulation in Cancer» within the Division of Molecular Genetics at the German Cancer Research Center (DKFZ) in Heidelberg, Germany. She is interested in immune modulatory mechanisms in the tumor microenvironment, with a focus on B-cell lymphoma and brain metastases.
Using innovative single-cell omics approaches, her team analyses the immune and stromal compartment of tumors to decipher tumor-supportive and immunosuppressive mechanisms and to suggest novel immunotherapy targets. The lab has established various coculture models of primary patient samples, as well as mouse models, that are used for studying disease biology as well as for pre-clinical testing of drugs. They recently identified the L-amino acid oxidase IL4I1 as a novel metabolic immune checkpoint that contributes to immune escape in cancer. The group has further demonstrated a novel role of IL-10 in preventing T-cell exhaustion and maintaining anti-tumor immunity.
After studying biology at the University of Constance, Germany and the University of Oregon, Eugene, USA, Dr. Seiffert obtained her PhD at the University of Tübingen, Germany, investigating the bone marrow microenvironment in hematopoietic malignancies. As a postdoctoral fellow, she continued her research at the University of Tübingen and the Fred Hutchinson Cancer Research Center in Seattle, USA, focusing on oncogenic signaling in malignant and stromal cells in cancer.
Zoom link (with one-time registration for the whole series) for attending remotely: https://go.epfl.ch/EPFLBioETalks
Instructions for 1st-year Ph.D. students who are under EDBB’s mandatory seminar attendance rule:
IF you are not attending in-person in the room, please make sure to
- send D. Reinhard a note before noon on seminar day, informing that you plan to attend the talk online, and
- be signed in on Zoom with a recognizable user name (not a pseudonym making it difficult or impossible to be identified).
Practical information
- Informed public
- Registration required
Organizer
- Prof. Li Tang, EPFL
Contact
- Institute of Bioengineering (IBI), Christina Mattsson