Monocyte-derived Dendritic Cells and Hematological Indexes in Glioblastoma Patients Who Underwent Immunotherapy

Author(s)

Carla Sanzochi Fogolin

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2023-05-05

Examining board members

Jose Alexandre Marzagao Barbuto; Ana Campa; Ramon Kaneno; Ana Paula Lepique

• Advisor: Jose Alexandre Marzagao Barbuto

Abstract

Glioblastoma (GBM) is the most invasive, undifferentiated, aggressive, and common central nervous system (CNS) tumor in adults. The standard treatment consists of maximum surgical resection followed by concurrent chemotherapy and radiotherapy, yet the median survival of patients is only 15 months, often with poor quality of life. This scenario indicates the need for the development of new therapeutic approaches, among which dendritic cell (DC)-based immunotherapy is a good candidate due to its unique ability to activate T lymphocytes. This approach is being tested in our laboratory, using allogenic DCs to vaccinate patients - instead of potentially dysfunctional autologous DCs. The DCs are fused with patient tumor cells, which provide the antigens and autologous MHC. This strategy has already been shown to be effective in reversing the dysfunctional state of DCs in melanoma and renal carcinoma, increasing their ability to activate CD4+ and CD8+ T lymphocytes. To evaluate whether this phenomenon also occurred in patients with GBM, DCs derived from patient monocytes (mo-DCs) were produced at various time points (before surgery, after surgery, and before each vaccine dose), and their ability to stimulate the proliferation of allogenic T lymphocytes from healthy donors was evaluated. The analyses found a large variability, both in the individual response of patients and between vaccine doses. Despite the heterogeneity of the responses, some interesting phenomena were observed: there was a decline in the ability to stimulate CD4+ and CD8+ T lymphocytes after surgery, suggesting that tumor removal alone can change the status of the immune system; frequently, the ability to stimulate T lymphocytes increased at the beginning of immunotherapy (between the 2nd and 4th doses), but this was not sustained. The mo-DC phenotype, although evaluated in a small number of samples, showed a tendency towards cells with low stimulatory activity, but not as clearly as what was seen in renal and breast tumors. In addition, men and women responded differently, with men showing DCs with greater allostimulatory capacity in early doses and women showing larger responses in later doses, but confirmation of this trend in a larger number of patients is needed. The granulocyte:lymphocyte and platelet:lymphocyte ratios, which in certain neoplasms have shown correlation with clinical evolution, also varied between doses in our patients, but, in general, an association between lower ratios and higher patient survival could be observed. Thus, we observed that surgery acutely and immunotherapy chronically affect the lympho-stimulatory function of patients\' mo-DCs. However, the great heterogeneity of the results prevents a definitive conclusion regarding their effects and their correlation with the clinical evolution of patients. (AU)

• FAPESP's process: 19/26089-4 - Study of tumor-specific T lymphocytes phenotypic profile in glioblastoma
• Grantee: Carla Sanzochi Fogolin
• Support Opportunities: Scholarships in Brazil - Master