CaMKK2 deletion causes increased accumulation of CD4+ TILs and an improved ratio of effector memory TILs to Tregs

Abstract

Objective Glioblastoma (GBM) is the most lethal primary brain tumor in adults. Although immunotherapy has been successful in some cancers, it has shown limited success in GBM. This is partially due to poor T cell infiltration, and because many T cells found in tumors are either exhausted or Tregs. Re-analysis of publicly available data has shown that CaMKK2 is more highly expressed in advanced brain tumors, and high CaMKK2 expression results in worse survival outcomes in GBM. Additionally, in survival studies that we performed, CaMKK2−/− mice showed an impressive survival phenotype that was dependent on the presence of CD8+ tumor infiltrating lymphocytes (TILs). The objective of our study was to investigate what is different about T cells found in the TME of CaMKK2−/− mice, and if this can explain the observed survival benefit. Methods We performed flow cytometry to determine the identities of T cells found in the tumors of CaMKK2−/− and WT mice. Results/Conclusions Our experiments show that there was a greater percentage of CD4+ TILs relative to CD8+ TILs in CaMKK2−/− mice, and this increase in percentage was due to increased accumulation of CD4+ TILs. Additionally, we found that there was greater accumulation of CD4+ and CD8+ effector memory TILs and a greater ratio of effector memory TILs to Tregs in CaMKK2−/− mice. The increased accumulation of the CD8+ effector memory TILs is particularly interesting because it is not simply explained by an increased accumulation of cells, as is the case with the CD4+ TILs. The increased accumulation of CD4+ TILs and greater ratio of effector memory TILs to Tregs is expected to have an anti-tumor effect. These findings make CaMKK2 a promising target to treat GBM.