EFFECT OF ANTI-PD-1 THERAPY COMBINATION ON TEMOZOLOMIDE IN MOUSE GLIOBLASTOMA

AbstractGlioblastoma (GBM) is the most common and aggressive primary brain tumor with a poor prognosis despite multimodal interventions. For brain tumors, immunotherapy has not yet fully proved their potential. The central nervous system has historically been regarded as an immune privileged organ, throwing doubt on application of immunotherapy to GBM. However, growing evidences suggest that immune cells can traverse the blood-brain barrier and affect immune responses in the brain. Although immunotherapy by programmed cell death protein 1 (PD-1) blockade has dramatically improved the survival rate of some types of cancer patients, its application to GBM still needs further investigation. To improve efficacy of immunotherapy, there have been many attempts for finding effective combination partner in several types of tumors. We hypothesized that TMZ could work synergistically with PD-1 blockade to generate a robust antitumor response against GBM. Here, we evaluated therapeutic responses of PD-1 blockade and its combination with temozolomide (TMZ) in mouse GBM model. PD-1 blockade remarkably showed long-term antitumor effects, and combined use of TMZ further improved survival rate. However, distinct working mechanisms operated in these two therapeutic strategies. Anti-PD-1 monotherapy significantly augmented the number of tumor-infiltrating lymphocytes and protected them from exhaustion. In comparison, TMZ combination abrogated these effects, suggesting that superior therapeutic efficacy did not originated from increased immune responses. Microarray experiments revealed that anti-PD-1 and combination groups differentially converted transcriptional programs, particularly emphasized by mutually exclusive functional annotation by ImmuneSigDB gene sets. Moreover, tumor rechallenge study showed that immunologic memory was generated only in the anti-PD-1 monotherapy group. Although TMZ did not facilitate anti-PD-1-mediated immune response or memory function, these data suggest that combined treatment of anti-PD-1 and TMZ exert robust antitumor efficacy with therapeutic benefits in GBM. In addition, our data suggest possibility of immunotherapy to be added in standard treatment modalities of GBM.