EXTH-07. NEOADJUVANT PD1 BLOCKADE ALTERS THE TUMOR MICROENVIRONMENT POST-SURGERY IN A PRECLINICAL MODEL OF RECURRENT GLIOBLASTOMA

Abstract

Abstract SIGNIFICANCE Clinical trials investigating neoadjuvant immunotherapy in recurrent glioblastoma patients have shown promising results. In this study, we aimed to assess the impact of neoadjuvant PD1 blockade on the tumor microenvironment after surgery using a relevant murine model of recurrent glioblastoma. OBJECTIVE Our objective was to investigate the effects of neoadjuvant PD1 inhibition on mouse survival and analyze the transcriptome and spatial genomic changes within the intratumoral immune populations following surgery. We compared these changes with those observed in adjuvant anti-PD1 treatment. RESULTS Through our established murine resection model of recurrent KR158 glioblastoma, we demonstrated that neoadjuvant PD1 inhibition prior to tumor debulking significantly improved mouse survival compared to adjuvant treatment. Transcriptome and spatial genomic analyses revealed notable alterations in immune exhaustion and activation pathway genes after neoadjuvant anti-PD1 treatment, distinguishing it from adjuvant anti-PD1 treatment. RNA and protein analyses indicated upregulation of various pathways, including PI3K/AKT, NOTCH, NK cell, MAPK, NF-kB, type II interferon, and TNF, in the neoadjuvant treatment group compared to the adjuvant anti-PD1 treatment group. Single-cell RNA sequencing analyses further revealed an increased proportion of CD8 T, NKT, and NK cells, accompanied by a decreased percentage of CD4 T cells in the neoadjuvant group. Importantly, we observed a significant enhancement in the interaction strength between CD8 T cells and all other immune cells in the neoadjuvant group compared to the adjuvant treatment group. CONCLUSIONS Our findings demonstrate distinct differences in immune cell populations and gene expression profiles between neoadjuvant and adjuvant anti-PD1 therapies in our murine recurrent glioblastoma resection model. These insights provide valuable understanding of the potential mechanisms underlying the divergent efficacy of neoadjuvant and adjuvant anti-PD1 therapies.