Retour sur le Congrès International d'Immunologie 2016, Melbourne, Australia par Maximilien Grandclaudon, lauréat d'une bourse de voyage CFCD.
ICI2016 – Summary – Grandclaudon Maximilien
Introduction:
Thanks of the CFCD fellowship I was able to attend the International Congress of Immunology 2016 that was held in Melbourne Australia. The congress covered a broad range of areas in of the immunology field. I mostly focused my attention on conferences talking about T cells and Cancer Immunology since these specific topics are all of major importance for my PhD and my laboratory. In consequences, in the following summary I selected one presentation in these fields that I found very interesting and innovative.
Ana Anderson: New insights into the dysfunctional T cell state
Controlling T cell state is key in order to develop successful therapeutic interventions in the field of immune therapy. In general in immunology it is well known that the function of a cell such as CD8 or CD4 T cell can be abolished when the cells are in a dysfunctional or exhausted state.
Such phenotypes are seen notably in chronic viral infections or inside the immune microenvironment of a tumor. Dysfunctional cells will harbor at their surface markers such as PD1, LAG3 or TIM3. It has been shown notably in cancer that blocking these molecules allows the restoration of an efficient T cell immunology and permitted drastic anti-tumoral effects. But these exhaustion markers are also very often expressed on activated cells. Therefore there is a need to study precisely intra tumoral T cell state to identify accurate “dysfunctional” signature and biomarkers different from activation signature, which would help to target specifically dysfunction without affecting the activation of T cells.
Ana Anderson and her team achieved this goal by sorting from CD8 Tumor infiltrating lymphocytes into 3 populations based On PD1 and TIM3 expression, Tim-3−PD-1− (DN, double negative), Tim-3−PD-1+ (SP, single positive), and Tim-3+PD-1+ (DP, double positive). DN TILs exhibit full effector function, SP TILs exhibit partial dysfunction, and DP TILs exhibit severe dysfunction, as reflected by the respective differences in their ability to produce effector cytokines. They then did the transcriptional profiles of these 3 subpopulations and found that one cluster of genes had features of both exhaustion and activation. Then they look for genes within this reduce list of genes that better discriminate the 3 different populations SP, DP and DN and found that metallothioneins which are intracellular zinc chaperones, are highly enriched in the most dysfunctional CD8+ TILs.
Then they demonstrate that targeted deletion of metallothioneins results in loss of T cell dysfunction and significantly reduced tumor growth despite no reduction in the expression of co-inhibitory molecules. By using single cell RNA sequencing they nicely show that their dysfunctional and activation modules were exclusive at the single cell level. Moreover, they showed that cells lacking the metallothioneins do not express the dysfunctional modules anymore. Finally, they demonstrate using CRISPR-Cas9 genome editing that GATA-3 is an important transcription factor in CD8 T cells driving their dysfunctional phenotype.
These results are key and open new ways to understand and target specifically T cell dysfunction, notably in the field of cancer immune-therapy without impacting T cell activation programs, which is important to have efficient immune responses.
ICI2016 – Summary – Grandclaudon Maximilien
Introduction:
Thanks of the CFCD fellowship I was able to attend the International Congress of Immunology 2016 that was held in Melbourne Australia. The congress covered a broad range of areas in of the immunology field. I mostly focused my attention on conferences talking about T cells and Cancer Immunology since these specific topics are all of major importance for my PhD and my laboratory. In consequences, in the following summary I selected one presentation in these fields that I found very interesting and innovative.
Ana Anderson: New insights into the dysfunctional T cell state
Controlling T cell state is key in order to develop successful therapeutic interventions in the field of immune therapy. In general in immunology it is well known that the function of a cell such as CD8 or CD4 T cell can be abolished when the cells are in a dysfunctional or exhausted state.
Such phenotypes are seen notably in chronic viral infections or inside the immune microenvironment of a tumor. Dysfunctional cells will harbor at their surface markers such as PD1, LAG3 or TIM3. It has been shown notably in cancer that blocking these molecules allows the restoration of an efficient T cell immunology and permitted drastic anti-tumoral effects. But these exhaustion markers are also very often expressed on activated cells. Therefore there is a need to study precisely intra tumoral T cell state to identify accurate “dysfunctional” signature and biomarkers different from activation signature, which would help to target specifically dysfunction without affecting the activation of T cells.
Ana Anderson and her team achieved this goal by sorting from CD8 Tumor infiltrating lymphocytes into 3 populations based On PD1 and TIM3 expression, Tim-3−PD-1− (DN, double negative), Tim-3−PD-1+ (SP, single positive), and Tim-3+PD-1+ (DP, double positive). DN TILs exhibit full effector function, SP TILs exhibit partial dysfunction, and DP TILs exhibit severe dysfunction, as reflected by the respective differences in their ability to produce effector cytokines. They then did the transcriptional profiles of these 3 subpopulations and found that one cluster of genes had features of both exhaustion and activation. Then they look for genes within this reduce list of genes that better discriminate the 3 different populations SP, DP and DN and found that metallothioneins which are intracellular zinc chaperones, are highly enriched in the most dysfunctional CD8+ TILs.
Then they demonstrate that targeted deletion of metallothioneins results in loss of T cell dysfunction and significantly reduced tumor growth despite no reduction in the expression of co-inhibitory molecules. By using single cell RNA sequencing they nicely show that their dysfunctional and activation modules were exclusive at the single cell level. Moreover, they showed that cells lacking the metallothioneins do not express the dysfunctional modules anymore. Finally, they demonstrate using CRISPR-Cas9 genome editing that GATA-3 is an important transcription factor in CD8 T cells driving their dysfunctional phenotype.
These results are key and open new ways to understand and target specifically T cell dysfunction, notably in the field of cancer immune-therapy without impacting T cell activation programs, which is important to have efficient immune responses.