Periodic Reporting for period 1 - LectiNet (Understanding Lectins' network language with chemical tools: new insights for immunological purposes.)
Periodo di rendicontazione: 2021-03-01 al 2023-02-28
Problem/Issue Being Addressed:
Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), capable of priming T-cell-mediated immune responses. They express numerous endocytic receptors on their surface that significantly influence the quality and magnitude of immune activation. However, a comprehensive molecular understanding of how to strategically co-engage these receptors to modulate immunity is still lacking.
The LectiNet project addresses this knowledge gap by developing a library of over 50 synthetic, structurally defined polymers specifically designed to systematically evaluate the co-engagement of DC surface receptors and its impact on DC maturation, activation, and functional reprogramming.
Importance for Society:
The ability to finely tune dendritic cell activation and steer immune responses is critical for the rational design of next-generation vaccines and immunotherapies. Tailoring immune activation is particularly important to meet the needs of different population groups, including children, the elderly, and immunocompromised individuals. Insights gained from this project could significantly advance the fields of personalized medicine and public health by enabling the creation of safer, more effective, and more precisely targeted vaccines and adjuvants.
Overall Objectives:
The primary objective of LectiNet is to explore dendritic cell receptor co-engagement using synthetic ligands and to decipher the complex combinatorial "language" that governs DC responses. By systematically dissecting these receptor interactions, the project aims to uncover design principles for modulating cellular immunity, ultimately enabling the development of more precise and effective immunotherapeutic strategies.
Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), capable of priming T-cell-mediated immune responses. They express numerous endocytic receptors on their surface that significantly influence the quality and magnitude of immune activation. However, a comprehensive molecular understanding of how to strategically co-engage these receptors to modulate immunity is still lacking.
The LectiNet project addresses this knowledge gap by developing a library of over 50 synthetic, structurally defined polymers specifically designed to systematically evaluate the co-engagement of DC surface receptors and its impact on DC maturation, activation, and functional reprogramming.
Importance for Society:
The ability to finely tune dendritic cell activation and steer immune responses is critical for the rational design of next-generation vaccines and immunotherapies. Tailoring immune activation is particularly important to meet the needs of different population groups, including children, the elderly, and immunocompromised individuals. Insights gained from this project could significantly advance the fields of personalized medicine and public health by enabling the creation of safer, more effective, and more precisely targeted vaccines and adjuvants.
Overall Objectives:
The primary objective of LectiNet is to explore dendritic cell receptor co-engagement using synthetic ligands and to decipher the complex combinatorial "language" that governs DC responses. By systematically dissecting these receptor interactions, the project aims to uncover design principles for modulating cellular immunity, ultimately enabling the development of more precise and effective immunotherapeutic strategies.
Our immune system protects us by detecting threats like viruses, bacteria, and cancer cells. Dendritic cells are one of the most important types of immune cells because they decide how the rest of the immune system should respond. However, scientists still do not fully understand how to "guide" dendritic cells to create the strongest and safest immune responses.
In the LectiNet project, we created a library of over 50 small, synthetic molecules that mimic the way germs naturally interact with dendritic cells. We tested these molecules in human immune cells in the lab and discovered that small changes in their structure could lead to very different immune reactions. From testing our library on dendritic cells we could draw some major conclusions:
Targeting Multiple Receptors at Once- We found that our synthetic molecules could successfully attach to and activate rare receptors on dendritic cells, even when other more common receptors were present. This shows that it is possible to design vaccines or treatments that precisely target less abundant parts of the immune system to fine-tune the response.
Each Molecule Creates a Unique Immune Response- Each different combination of sugars and immune activators on our synthetic molecules caused dendritic cells to behave in slightly different ways. Some molecules made the cells show stronger "activation signals," which are important for telling the rest of the immune system to respond.
Soluble Molecules Are Less Powerful Adjuvants- While our soluble molecules were good at activating dendritic cells, they did not strongly trigger the release of immune system messenger molecules called cytokines. This suggests that, in their current form, these molecules may need further modification (for example, by being made into particles) before being used as vaccine adjuvants in living organisms.
To overcome the minor immonogenic power of the soluble polimers, we also created a particulate, stiffer vaccine candidate that combined two different signals to better activate the immune system. We tested this vaccine in mice with an aggressive form of melanoma (a type of skin cancer). The vaccine was able to reach the right areas of the body, activate important immune cells, and trigger an antibody response.
Through this work, LectiNet has taken important steps toward designing better vaccines and immune therapies that could, in the future, help treat diseases like cancer and infections more effectively and safely.
In the LectiNet project, we created a library of over 50 small, synthetic molecules that mimic the way germs naturally interact with dendritic cells. We tested these molecules in human immune cells in the lab and discovered that small changes in their structure could lead to very different immune reactions. From testing our library on dendritic cells we could draw some major conclusions:
Targeting Multiple Receptors at Once- We found that our synthetic molecules could successfully attach to and activate rare receptors on dendritic cells, even when other more common receptors were present. This shows that it is possible to design vaccines or treatments that precisely target less abundant parts of the immune system to fine-tune the response.
Each Molecule Creates a Unique Immune Response- Each different combination of sugars and immune activators on our synthetic molecules caused dendritic cells to behave in slightly different ways. Some molecules made the cells show stronger "activation signals," which are important for telling the rest of the immune system to respond.
Soluble Molecules Are Less Powerful Adjuvants- While our soluble molecules were good at activating dendritic cells, they did not strongly trigger the release of immune system messenger molecules called cytokines. This suggests that, in their current form, these molecules may need further modification (for example, by being made into particles) before being used as vaccine adjuvants in living organisms.
To overcome the minor immonogenic power of the soluble polimers, we also created a particulate, stiffer vaccine candidate that combined two different signals to better activate the immune system. We tested this vaccine in mice with an aggressive form of melanoma (a type of skin cancer). The vaccine was able to reach the right areas of the body, activate important immune cells, and trigger an antibody response.
Through this work, LectiNet has taken important steps toward designing better vaccines and immune therapies that could, in the future, help treat diseases like cancer and infections more effectively and safely.
Progress Beyond the State of the Art:
For the first time, a fully synthetic library has been developed to systematically probe the co-engagement of C-type lectin receptors (CLRs) and Toll-like receptors (TLRs) on dendritic cells. In vitro evaluation of this library demonstrated that each combination of ligands generates a distinct dendritic cell activation profile, highlighting the nuanced role of receptor co-engagement in immune modulation. LectiNet represents a highly interdisciplinary effort, bridging synthetic chemistry and immunology to provide fundamental insights into the role of glycans in regulating immune responses.
Expected Results Until the End of the Project:
LectiNet is expected to define design principles for constructing synthetic immunomodulators that precisely manipulate dendritic cell activation pathways. The project will further advance translational applications by developing polymer-based platforms capable of enhancing cellular immunity, with a particular focus on applications in immunotherapy and vaccine development.
Potential Impacts:
LectiNet aims to open new avenues in the design of therapeutic vaccines and immunotherapies that fully exploit cellular immunity. For example, findings from my latest publication in ACS Nano demonstrate that incorporating specific glycans into vaccine constructs can not only enhance antigen-presenting cell (APC) uptake but also actively reprogram immune responses toward desired outcomes. This could significantly impact the future design of cancer vaccines and other immunotherapeutic strategies, leading to more effective and targeted treatments.
Socio-Economic Impact and Wider Societal Implications:
The insights generated by LectiNet have the potential to improve human health by enabling the creation of safer, more efficacious vaccines and immunotherapies tailored to diverse patient populations. In the long term, this knowledge could contribute to reducing healthcare costs associated with chronic infections, cancer, and age-related immune dysfunctions, thus offering substantial socio-economic benefits and enhancing public health outcomes globally.
For the first time, a fully synthetic library has been developed to systematically probe the co-engagement of C-type lectin receptors (CLRs) and Toll-like receptors (TLRs) on dendritic cells. In vitro evaluation of this library demonstrated that each combination of ligands generates a distinct dendritic cell activation profile, highlighting the nuanced role of receptor co-engagement in immune modulation. LectiNet represents a highly interdisciplinary effort, bridging synthetic chemistry and immunology to provide fundamental insights into the role of glycans in regulating immune responses.
Expected Results Until the End of the Project:
LectiNet is expected to define design principles for constructing synthetic immunomodulators that precisely manipulate dendritic cell activation pathways. The project will further advance translational applications by developing polymer-based platforms capable of enhancing cellular immunity, with a particular focus on applications in immunotherapy and vaccine development.
Potential Impacts:
LectiNet aims to open new avenues in the design of therapeutic vaccines and immunotherapies that fully exploit cellular immunity. For example, findings from my latest publication in ACS Nano demonstrate that incorporating specific glycans into vaccine constructs can not only enhance antigen-presenting cell (APC) uptake but also actively reprogram immune responses toward desired outcomes. This could significantly impact the future design of cancer vaccines and other immunotherapeutic strategies, leading to more effective and targeted treatments.
Socio-Economic Impact and Wider Societal Implications:
The insights generated by LectiNet have the potential to improve human health by enabling the creation of safer, more efficacious vaccines and immunotherapies tailored to diverse patient populations. In the long term, this knowledge could contribute to reducing healthcare costs associated with chronic infections, cancer, and age-related immune dysfunctions, thus offering substantial socio-economic benefits and enhancing public health outcomes globally.