Periodic Reporting for period 1 - TESTIMONY (Tumor Endothelial Cells: Gatekeepers Of Anti-Tumor Immunity)
Okres sprawozdawczy: 2020-05-01 do 2022-04-30
Cancer cells need nutrients to sustain growth. Because blood vessels function as conduits to supply nutrients, cancer cells stimulate angiogenesis. Hence, since the 70’s, disrupting the vascular supply has been postulated to starve tumors. However, tumor blood vessels also affect tumor progression by carrying immune cells to and from the tumor, and likely by influencing immune surveillance, though the latter has been largely overlooked in cancer. Blood vessels are lined by a monolayer of cells, called endothelial cells (ECs). Recent data show that ECs can affect immune surveillance, also in the tumor. Indeed, the tumor vasculature is a major barrier for lymphocytes because it can upregulate immunosuppressive molecules and downregulate adhesion molecules, all together hindering tumor-reactive T cell activation and infiltration into the tumor and fostering an immunosuppressive environment that allows tumors to evade host immunosurveillance.
A promising approach to reinvigorate the anti-tumor immune response is blockade of immune checkpoint proteins to break immune tolerance. Immune checkpoint proteins are usurped by tumors to escape T cell mediated lysis. The best characterized immune checkpoint proteins are the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the programmed death 1 receptors (PD1). Administration of monoclonal antibodies targeting CTLA-4, PD1 or programmed death ligand-1 (PD-L1) shows remarkable anti-tumor effects in the clinic. Nonetheless, resistance to immune checkpoint protein blockade is a formidable problem, in part due to immune suppression, insufficient immune cell recruitment and tolerance to tumor associated antigens. Identifying fundamental molecular mechanisms which affect potent T cell infiltration and translating these insights by developing new approaches to improve immunotherapy and to overcome immunotherapy resistance, are tremendous unmet medical needs.
PD-L1 has been described to be upregulated on tumor ECs, but how this contributes to tumor immunity and whether it affects immunotherapy response requires further elucidation. Because PD-L1:PD1 interactions impair T cell proliferation, cytokine production and survival, PD-L1 on tumor ECs could impair T cell-mediated anti-tumor immunity even before T cells encounter any other tumor-associated cell. The endothelium is being increasingly viewed as a critical non-hematopoietic component of the immune system. Given the strategic “1st line” location of tumor ECs and increased T cell recruitment during successful immune checkpoint blockade, it raises the question if at least part of the success of immunotherapy based on immune checkpoint blockade, is dependent on tumor EC immunity. This project has the potential to unravel previously unrecognized mechanisms through which non-hematopoietic cells, in this case tumor ECs, might be a major contributor to immunotherapy success, thus encouraging further clinical projects to investigate whether tumor ECs might be of therapeutic interest in immunotherapy decisions.
The central hypothesis for this project is that PD-L1 on tumor ECs impairs T cell-mediated anti-tumor immunity by impairing the function of recruited T cells and affects, in part, the success of immune checkpoint blockade.
A promising approach to reinvigorate the anti-tumor immune response is blockade of immune checkpoint proteins to break immune tolerance. Immune checkpoint proteins are usurped by tumors to escape T cell mediated lysis. The best characterized immune checkpoint proteins are the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the programmed death 1 receptors (PD1). Administration of monoclonal antibodies targeting CTLA-4, PD1 or programmed death ligand-1 (PD-L1) shows remarkable anti-tumor effects in the clinic. Nonetheless, resistance to immune checkpoint protein blockade is a formidable problem, in part due to immune suppression, insufficient immune cell recruitment and tolerance to tumor associated antigens. Identifying fundamental molecular mechanisms which affect potent T cell infiltration and translating these insights by developing new approaches to improve immunotherapy and to overcome immunotherapy resistance, are tremendous unmet medical needs.
PD-L1 has been described to be upregulated on tumor ECs, but how this contributes to tumor immunity and whether it affects immunotherapy response requires further elucidation. Because PD-L1:PD1 interactions impair T cell proliferation, cytokine production and survival, PD-L1 on tumor ECs could impair T cell-mediated anti-tumor immunity even before T cells encounter any other tumor-associated cell. The endothelium is being increasingly viewed as a critical non-hematopoietic component of the immune system. Given the strategic “1st line” location of tumor ECs and increased T cell recruitment during successful immune checkpoint blockade, it raises the question if at least part of the success of immunotherapy based on immune checkpoint blockade, is dependent on tumor EC immunity. This project has the potential to unravel previously unrecognized mechanisms through which non-hematopoietic cells, in this case tumor ECs, might be a major contributor to immunotherapy success, thus encouraging further clinical projects to investigate whether tumor ECs might be of therapeutic interest in immunotherapy decisions.
The central hypothesis for this project is that PD-L1 on tumor ECs impairs T cell-mediated anti-tumor immunity by impairing the function of recruited T cells and affects, in part, the success of immune checkpoint blockade.
This project studies, using state-of-the-art inducible endothelial cell-specific PD-L1 knock-out mice, the effect of PD-L1 expression by tumor ECs on anti-tumor immunity and validate the cellular and molecular mechanisms behind it using human tumor ECs in vitro. Moreover, it studies the therapeutic efficacy of PD-L1 blockade in mice with EC-selective PD-L1 deficiency in a tumor model which shows partial responsiveness to anti-PD-L1 treatment.
This project is the first multidisciplinary study demonstrating the effect of PD-L1 deficiency in tumor ECs on tumor growth and immunity. It is the first to identify the mechanisms by which PD-L1 on tumor ECs modulates anti-tumor immunity in different stages of tumor development, and how inflammatory T cells are at the crossroads of tumor angiogenesis and immunity in preclinical tumor models. Indeed, the project has uncovered that PD-L1 is a central regulator in T cell-mediated tumor immunity, affecting tumor development through regulation of angiogenesis as well as pro-inflammatory T cell skewing. Assays using primary human cells showed that PD-L1 on ECs can act as a selective gatekeeper for pro- vs. anti-inflammatory T cells, suggesting that it modulates tumor immunity through multiple mechanisms.
This project is the first multidisciplinary study demonstrating the effect of PD-L1 deficiency in tumor ECs on tumor growth and immunity. It is the first to identify the mechanisms by which PD-L1 on tumor ECs modulates anti-tumor immunity in different stages of tumor development, and how inflammatory T cells are at the crossroads of tumor angiogenesis and immunity in preclinical tumor models. Indeed, the project has uncovered that PD-L1 is a central regulator in T cell-mediated tumor immunity, affecting tumor development through regulation of angiogenesis as well as pro-inflammatory T cell skewing. Assays using primary human cells showed that PD-L1 on ECs can act as a selective gatekeeper for pro- vs. anti-inflammatory T cells, suggesting that it modulates tumor immunity through multiple mechanisms.
Immunotherapy, and more specifically immune checkpoint blockade, currently receives a huge amount of attention for their potential as an anti-cancer drug. However, there are great caveats in the knowledge of their therapeutic mechanism which is exemplified by the large fraction of patients which are resistant to this class of drugs. Through a multi-angled approach, this project will unravel the role and dynamics of tumor EC-expressed PD-L1 in the tumor immune response relative to the cancer- expressed PD-L1 and uncover its contribution to anti-tumor immunity and response to immune checkpoint blockade, which could provide a rationale for (the exploration of) novel responsiveness assessment in human tumor biopsies, combination therapies or treatment regimes. Thus, this project represents a major part of medical and societal concerns.