Samenvatting
Anti-Neuropilin-1 Nanobodies as novel cancer therapeutics
Neuropilin-1 (NRP-1) is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF) family members that can be expressed on cancer cells and tumor-infiltrating myeloid, endothelial and lymphoid cells. It has been linked to a tumor-promoting environment upon interaction with semaphorin 3A (Sema3A). Nanobodies (Nbs) targeting NRP-1 were generated for their potential to hamper the NRP-1/Sema3A interaction and their impact on colorectal carcinoma (CRC) development was evaluated in vivo through the generation of anti-NRP-1-producing CRC cells. We observed that tumor growth was significantly delayed and survival prolonged when the anti-NRP-1 Nbs were produced in vivo. We further analyzed the tumor microenvironment and observed that the pro-inflammatory MHC-IIhigh/trophic MHC-IIlow macrophage ratio was increased in tumors that produce anti-NRP-1 Nbs. This finding was further corroborated by an increase in the expression of genes associated with MHC-IIhigh macrophages and a decrease in the expression of MHC-IIlow macrophage-associated genes in the macrophage pool sorted from anti-NRP-1 Nb-producing tumors. Moreover, we observed a significantly higher percentage of tumor-associated antigen-specific CD8+ T cells in tumors producing anti-NRP-1 Nbs. These data demonstrate that an intratumoral expression of NRP-1/Sema3A blocking biologicals increases anti-tumor immunity. However, these data were generated in lentivirally-engineered cells which do not represent the physiological reality. Henceforth, we generated functionalized and optimized version of the Nbs for systemic injection, aimed at increasing the potency of the Nbs within the tumor microenvironment. Multivalent Nb constructs increases the avidity of the Nbs for their target while extending the lifetime of the constructs within circulation. These novel constructs promise off-the-shelf biologicals that will revert the immune suppressive tumor microenvironment as a novel cancer therapy and that may be complementary to or even synergistic with other immunotherapies
Neuropilin-1 (NRP-1) is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF) family members that can be expressed on cancer cells and tumor-infiltrating myeloid, endothelial and lymphoid cells. It has been linked to a tumor-promoting environment upon interaction with semaphorin 3A (Sema3A). Nanobodies (Nbs) targeting NRP-1 were generated for their potential to hamper the NRP-1/Sema3A interaction and their impact on colorectal carcinoma (CRC) development was evaluated in vivo through the generation of anti-NRP-1-producing CRC cells. We observed that tumor growth was significantly delayed and survival prolonged when the anti-NRP-1 Nbs were produced in vivo. We further analyzed the tumor microenvironment and observed that the pro-inflammatory MHC-IIhigh/trophic MHC-IIlow macrophage ratio was increased in tumors that produce anti-NRP-1 Nbs. This finding was further corroborated by an increase in the expression of genes associated with MHC-IIhigh macrophages and a decrease in the expression of MHC-IIlow macrophage-associated genes in the macrophage pool sorted from anti-NRP-1 Nb-producing tumors. Moreover, we observed a significantly higher percentage of tumor-associated antigen-specific CD8+ T cells in tumors producing anti-NRP-1 Nbs. These data demonstrate that an intratumoral expression of NRP-1/Sema3A blocking biologicals increases anti-tumor immunity. However, these data were generated in lentivirally-engineered cells which do not represent the physiological reality. Henceforth, we generated functionalized and optimized version of the Nbs for systemic injection, aimed at increasing the potency of the Nbs within the tumor microenvironment. Multivalent Nb constructs increases the avidity of the Nbs for their target while extending the lifetime of the constructs within circulation. These novel constructs promise off-the-shelf biologicals that will revert the immune suppressive tumor microenvironment as a novel cancer therapy and that may be complementary to or even synergistic with other immunotherapies
| Originele taal-2 | English |
|---|---|
| Status | Published - 2022 |
| Evenement | 4th Research Day in Tumor Immunology and Immunotherapy - Irish College, Janseniusstraat 1, 3000 , Leuven, Belgium Duur: 18 okt 2022 → 18 okt 2022 https://gbiomed.kuleuven.be/english/research/50488876/53773436/laboratory-for-tumor-immunology-and-immunotherapy/4th-research-day |
Conference
| Conference | 4th Research Day in Tumor Immunology and Immunotherapy |
|---|---|
| Land/Regio | Belgium |
| Stad | Leuven |
| Periode | 18/10/22 → 18/10/22 |
| Internet adres |