Publication
Patterns of T cell co-stimulation and co-inhibition in tumor microenvironment conditions, in vitro
| Summary: | T cells (helper and cytotoxic) are present within the tumor microenvironment and constitute viable targets for immunotherapeutic approaches against cancer, either by adoptive T cell transfer or by the use of monoclonal antibodies. The activation, differentiation, function and survival of those T cells comprehends a complex process and it is regulated by co-stimulatory and co-inhibitory receptors which modulate the initial T cell receptor (TCR) signal, increasing or hindering their anti-tumor function, respectively. Furthermore, various factors secreted by tumor cells or non-lymphoid stromal cells are believed to mostly downmodulate T cell responses. In this work the patterns of expression of co-signaling molecules on T cells were assessed using peripheral blood mononuclear cells (PBMCs) from healthy donors cultured with transforming growth factor (TGF-β), in order to mimic one of the major immunosuppressive stimuli of the tumor microenvironment. Noteworthy, all herein reported effects of TGF-β were entirely dependent on the subsequent T cell activation by an antibody against the CD3ε chain that is part of the TCR complex. While co-inhibitory receptors such as CTLA4 and PD1 were upregulated, PD-L1, TIGIT and TIM3 (also co-inhibitory) had their expression decreased. The transcription factor FOXP3, associated with the regulatory T cell phenotype, was upregulated by TGF-β. For co-activating receptors, the same condition upregulated 4-1BB, CD30 and CD28 expression, whereas it decreased OX40, ICOS and DNAM1 and did not it interfere with CD27 or LIGHT expression. Moreover, alongside TGF-β and anti-CD3, recombinant proteins, such as 4-1BB or OX40 ligand, were added, in order to simulate potential therapeutic strategies using agonistic 4-1BB or OX40 antibodies. It was shown that even though they could induce expression of co-stimulatory receptors such as OX40, CD27 and CD28, there was also CTLA4, PD-1 and TIGIT upregulation. It seems crucial to unravel the details of the dynamics of the expression of co-signaling molecules on T cells to improve existent immunotherapies and design new approaches able to circumvent the immunosuppressive environment, created not only by tumor or stromal cells, but also by immune cells themselves. |
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| Main Authors: | Guerra, Luana Frias, 1992- |
| Subject: | Biologia molecular Cancro Células T Imunoterapia Teses de mestrado - 2015 |
| Year: | 2015 |
| Country: | Portugal |
| Document type: | master thesis |
| Access type: | open access |
| Associated institution: | Universidade de Lisboa |
| Language: | English |
| Origin: | Repositório da Universidade de Lisboa |
| Summary: | T cells (helper and cytotoxic) are present within the tumor microenvironment and constitute viable targets for immunotherapeutic approaches against cancer, either by adoptive T cell transfer or by the use of monoclonal antibodies. The activation, differentiation, function and survival of those T cells comprehends a complex process and it is regulated by co-stimulatory and co-inhibitory receptors which modulate the initial T cell receptor (TCR) signal, increasing or hindering their anti-tumor function, respectively. Furthermore, various factors secreted by tumor cells or non-lymphoid stromal cells are believed to mostly downmodulate T cell responses. In this work the patterns of expression of co-signaling molecules on T cells were assessed using peripheral blood mononuclear cells (PBMCs) from healthy donors cultured with transforming growth factor (TGF-β), in order to mimic one of the major immunosuppressive stimuli of the tumor microenvironment. Noteworthy, all herein reported effects of TGF-β were entirely dependent on the subsequent T cell activation by an antibody against the CD3ε chain that is part of the TCR complex. While co-inhibitory receptors such as CTLA4 and PD1 were upregulated, PD-L1, TIGIT and TIM3 (also co-inhibitory) had their expression decreased. The transcription factor FOXP3, associated with the regulatory T cell phenotype, was upregulated by TGF-β. For co-activating receptors, the same condition upregulated 4-1BB, CD30 and CD28 expression, whereas it decreased OX40, ICOS and DNAM1 and did not it interfere with CD27 or LIGHT expression. Moreover, alongside TGF-β and anti-CD3, recombinant proteins, such as 4-1BB or OX40 ligand, were added, in order to simulate potential therapeutic strategies using agonistic 4-1BB or OX40 antibodies. It was shown that even though they could induce expression of co-stimulatory receptors such as OX40, CD27 and CD28, there was also CTLA4, PD-1 and TIGIT upregulation. It seems crucial to unravel the details of the dynamics of the expression of co-signaling molecules on T cells to improve existent immunotherapies and design new approaches able to circumvent the immunosuppressive environment, created not only by tumor or stromal cells, but also by immune cells themselves. |
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