Ph. D. Project
Title:
The combined effect of NRP-1 inhibition and radiotherapy on the immune response of medulloblastoma: a new treatment perspective
Dates:
2024/10/01 - 2027/09/30
Supervisor(s):
Description:
Medulloblastoma is the most common tumour of the central nervous system in children, accounting for 20% of paediatric brain tumours. Current treatments consist of surgery followed by irradiation and chemotherapy. Despite a high survival rate, current treatments remain aggressive, particularly to combat metastases and the risk of recurrence. The therapeutic consequences are significant morbidity, with significant impairment of cognitive and endocrine functions. It is therefore necessary to find treatments that are more selective and less aggressive towards healthy tissue, and ultimately more effective, in order to improve the quality of life of these young patients and increase the cure rate.
Optimising treatments means taking into account the heterogeneity and intrinsic sensitivity of tumour tissue. To do this, it is essential to understand the mechanisms of resistance and recurrence, resulting in particular from the immune component. In recent years, it has been shown that neuropilin-1 (NRP1) is crucial for regulating the immune response, in both normal and pathological conditions such as cancer. Indeed, in cancer, NRP1 has been shown to be highly expressed by tumour-infiltrating CD4+ lymphocytes (TILs). In addition, NRP1 signalling has been implicated in increasing the number of regulatory T cells, which are essential for maintaining peripheral tolerance and regulating immune responses, as well as potentiating their function. In addition to its role as an immune regulator, NRP1 is also involved in immune cell migration. NRP1 has been shown to control the recruitment of tumour-associated macrophages (TAMs). Inhibition of NRP1 within macrophages/microglial cells leads to a reduction in their pro-angiogenic and immunosuppressive effects and leads to inhibition of tumour growth and metastasis as recently shown in the work of Miyauchi et al in adult glioma progression (Miyauchi et al., 2016; Miyauchi et al., 2018). We recently showed that NRP1 inhibition of medulloblastoma stem cells decreased their stemness potential (Gong et al., 2018). Moreover, targeting NRP1 in combination with radiotherapy showed improved in vitro radiosensitivity in different medulloblastoma models of SHH subgroups (Daoy cell lines) or 3/4 subgroups (D283 or D341 cell lines). Similar results were obtained in an orthotopic xenograft model but with a shorter-lasting effect (Douyère et al, Cancer Cell International 2022). However, for these studies we used immunosuppressed conventional nude mice in which the immune component is relatively depleted of lymphocyte cells. Although our previous results are relatively encouraging for the inhibition of NRP1 in combination with radiotherapy, no preclinical results are available taking into account the immune cell response in this potential therapeutic approach in medulloblastoma.We are therefore proposing a new thesis project to validate the inhibition of NRP1 in combination with radiotherapy in medulloblastoma, taking into account the immune component, using medulloblastoma microarray models and humanised mice xenografted orthotopically with human medulloblastoma cellsor mouse models of spontaneous medulloblastoma (Ptch1 +/- ). Finally, we hope to provide answers as to the involvement of NRP1 in the progression of medulloblastoma via the immune system and to propose an alternative therapeutic approach to conventional treatment that is less harmful to young patients.
Optimising treatments means taking into account the heterogeneity and intrinsic sensitivity of tumour tissue. To do this, it is essential to understand the mechanisms of resistance and recurrence, resulting in particular from the immune component. In recent years, it has been shown that neuropilin-1 (NRP1) is crucial for regulating the immune response, in both normal and pathological conditions such as cancer. Indeed, in cancer, NRP1 has been shown to be highly expressed by tumour-infiltrating CD4+ lymphocytes (TILs). In addition, NRP1 signalling has been implicated in increasing the number of regulatory T cells, which are essential for maintaining peripheral tolerance and regulating immune responses, as well as potentiating their function. In addition to its role as an immune regulator, NRP1 is also involved in immune cell migration. NRP1 has been shown to control the recruitment of tumour-associated macrophages (TAMs). Inhibition of NRP1 within macrophages/microglial cells leads to a reduction in their pro-angiogenic and immunosuppressive effects and leads to inhibition of tumour growth and metastasis as recently shown in the work of Miyauchi et al in adult glioma progression (Miyauchi et al., 2016; Miyauchi et al., 2018). We recently showed that NRP1 inhibition of medulloblastoma stem cells decreased their stemness potential (Gong et al., 2018). Moreover, targeting NRP1 in combination with radiotherapy showed improved in vitro radiosensitivity in different medulloblastoma models of SHH subgroups (Daoy cell lines) or 3/4 subgroups (D283 or D341 cell lines). Similar results were obtained in an orthotopic xenograft model but with a shorter-lasting effect (Douyère et al, Cancer Cell International 2022). However, for these studies we used immunosuppressed conventional nude mice in which the immune component is relatively depleted of lymphocyte cells. Although our previous results are relatively encouraging for the inhibition of NRP1 in combination with radiotherapy, no preclinical results are available taking into account the immune cell response in this potential therapeutic approach in medulloblastoma.We are therefore proposing a new thesis project to validate the inhibition of NRP1 in combination with radiotherapy in medulloblastoma, taking into account the immune component, using medulloblastoma microarray models and humanised mice xenografted orthotopically with human medulloblastoma cellsor mouse models of spontaneous medulloblastoma (Ptch1 +/- ). Finally, we hope to provide answers as to the involvement of NRP1 in the progression of medulloblastoma via the immune system and to propose an alternative therapeutic approach to conventional treatment that is less harmful to young patients.
Keywords:
Paediatric brain tumours, medulloblastoma, neuropilin-1, immune cells
Department(s):
| Biology, Signals and Systems in Cancer and Neuroscience |
Publications: