Abstract 2667: CaMKK2 knockout in mice challenged by orthotopic GBM leads to upregulation of MHC II on TAMs and an increase in accumulation of CD4+ TILs

Abstract

Glioblastoma (GBM) is the most lethal primary brain tumor in adults, with the median survival time for GBM patients being only about 15 months. Although immunotherapy treatments have been successful in more immunogenic tumors, it has shown very limited success in GBM. This could be because it is difficult for T cells to infiltrate the tumor, and the tumors have a very immunosuppressive tumor microenvironment (TME) that can often consist of up to about 30 percent tumor associated macrophages (TAMs) by mass. Thus, two ways of possibly improving immunotherapy treatments on GBMs would be to increase the number of tumor infiltrating lymphocytes (TILs) present, and to target tumor-supportive cells such as TAMs. Calmodulin Dependent Protein Kinase Kinase 2 (CaMKK2) is a gene that has been shown to be highly expressed in myeloid cells and is known to alter their phenotype. Recent studies in breast cancer have shown that myeloid cells adopt a more immunostimulatory phenotype in murine knockout CaMKK2 models. However, it is not well understood how CaMKK2 causes this immunosuppressive effect and warrants further exploration. The data from our experiments help to answer this question. High-dimensional flow cytometry with 15 parameters was used in order to determine the identities of immune cells found in the tumor of wildtype and CaMKK2-/- mice. The results of our experiments show that there appear to be more CD4+ TILs present in the TME of knockout mice and that there is an increase in MHC II expression on TAMs found in knockout mice. Since CD4+ TILs recognize peptides presented on MHC II molecules, and there is an increase in the number of CD4+ TILs and expression of MHC II on TAMs in knockout mice, we hypothesize that a stronger immune response could be instigated against the tumor. Therefore, it can be concluded that a possible reason that knocking out CaMKK2 leads to a less immunosupressive TME is because MHC II expression on TAMs is upregulated, and the number of CD4+ TILs in the TME is increased. Whether or not the increase in MHC II expression causes the increase in the number CD4+ TILs requires further exploration. This makes CaMKK2 a promising therapeutic target to treat tumors with immunosuppressive TMEs such as GBM. Citation Format: Molly A. Chakraborty, William H. Tomaszewski, Jessica Waibl Polania, Lauren S. Riley, Luigi Racioppi, Luis A. Sanchez-Perez, John H. Sampson. CaMKK2 knockout in mice challenged by orthotopic GBM leads to upregulation of MHC II on TAMs and an increase in accumulation of CD4+ TILs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2667.