All right, we'll introduce the next speaker, Derek Lee, who's presenting on systemic and local immune suppression in patients with high-grade meningiomas. And Derek is a recipient of a Young Neurosurgeons Medical Student Abstract Award. Great work. I would like to thank the AANS Scientific Meeting Committee for the invitation to present my research on systemic and local immunosuppression in patients with high-grade meningiomas. I have no disclosures. Meningiomas are one of the most common primary, or is the most common primary, intracranial tumor, accounting for over one-third of all brain tumors. Although most are classified as WHO grade 1, about 20% are grade 2 and 3% are grade 3. Shown here are the progression-free and overall survival curves of patients with meningioma. And as you can see, patients with higher-grade tumors have significantly worse outcomes. One therapeutic approach that has gained traction in cancer treatment is immunotherapy. The immune system has the ability to target and destroy tumor cells through interactions between cytotoxic CD8 T-cells and the tumor cells. The role of immunotherapy is to stimulate and support the immune system as it fights cancer. However, cancer cells have evolved mechanisms to counteract and evade the immune surveillance, these mechanisms known as immune checkpoints. There are many available, but the two that are best studied are the PD-1, PD-L1 pathway and the CD80 CTLA-4 pathway. And so when activated immune cells become exhausted in the inflammatory microenvironment of the tumor, these immune checkpoints are upregulated. And our study focuses on the PD-L1 checkpoint, which has been shown to induce T-cell energy and apoptosis through binding with PD-1. Consequently, drugs have been developed to inhibit these immune checkpoints, and multiple clinical trials have demonstrated favorable outcomes in various cancers. Of note, there's currently a trial undergoing right now looking at nevolumab use in recurrent high-grade meningiomas. And so the question that we wanted to investigate was whether meningiomas also expressed these immune checkpoints. This is a study done by Hahn et al., which demonstrated that PD-L1 was expressed in meningiomas and that it was primarily expressed by tumor cells as opposed to infiltrating macrophages. They also looked at the impact on survival and found that intratumoral PD-L1 was associated with overall survival but not progression-free survival. Of note, they did choose a cohort of patients that was enriched in grade 2 and 3 meningiomas. Another study done by Du et al. also examined PD-L1 within meningiomas. And again, they confirmed that PD-L1 was expressed with higher levels of PD-L1 in higher-grade tumors. However, they did not find any significant association between intratumoral PD-L1 expression with progression-free or overall survival. So overall, the data is convincing that PD-L1 is expressed within meningiomas, but its significance is still unclear. So therefore, we sought to investigate the extent of systemic and local immunosuppression in meningiomas to assess the potential benefit for immune checkpoint inhibitors in the treatment of high-grade meningiomas. Here we present our cohort of patients. We were able to obtain peripheral blood samples and tissue sections from 53 patients. 18 of them had grade 1, 25 grade 2, and 10 grade 3 tumors. And about two-thirds of our patients received gross total resection. And on the right, we demonstrate that our cohort of patients' outcomes by grade are consistent with previous literature. And so we did immunohistochemistry staining on our patients using the PD-L1 SP142 antibody. And we again confirmed that PD-L1 was expressed in the meningiomas and that higher-grade tumors had higher levels of PD-L1 expression. We also did immunofluorescent staining using PD-L1 and CD68 and confirmed that the PD-L1 was from primarily non-immune cells. So this is consistent with the findings from Han et al. When we looked at survival, we found that intratumoral PD-L1 did not significantly associate with progression-free survival. This was consistent with the findings from Du et al. We also know that these immune checkpoints are not only expressed in the tumor microenvironment. Various cell types throughout the systemic immune compartment also express PD-L1. So prior work in our lab has demonstrated an upregulation of peripheral myeloid PD-L1 in patients with glioblastoma. And in patients who received autologous heat shock protein vaccination, increased peripheral myeloid PD-L1 was associated with worse overall survival. So given these findings, we wanted to also investigate the immune profile, the systemic immune profile in patients with meningiomas. So the first thing we looked at was peripheral myeloid PD-L1, and we found that in grade 3 tumors, there was an increase of peripheral myeloid PD-L1 compared to lower grades. In addition, using a cutoff of 10%, we found peripheral myeloid PD-L1 to be predictive of a higher grade tumor. We also examined other suppressive immune populations, and we found that peripheral MDSCs were increased in patients with grade 2 and 3 tumors, but did not find a significant correlation with peripheral Treg with grades. We then stratified patients into high and low groups around the median to look at the impact on survival, and we found that peripheral myeloid PD-L1 and peripheral MDSC abundance did not correlate with progression-free survival. Knowing that PD-L1 was expressed within these tumors, we wanted to further characterize the T cell infiltrate, and we noticed that there was a significant number of T cells in these tumors, and by counting the amount of cells from five high-powered fields, we noted that grade 2 and 3 tumors had significantly higher amounts of CD3 infiltration compared to lower grade. We also examined PD-1 expression, but did not find a significant correlation with grades. We looked at FOXP3 through immunohistochemistry. This is a transcription factor that's activated in Tregs, and we found that grade 3 meningiomas were significantly higher in Treg infiltration. So, again, we stratified patients into high and low groups around the median to look at survival, and we found that increased T cell infiltration was associated with worse survival. Of note, we only included patients with grade 2 and 3 meningiomas as our grade 1 tumors had very low CD3 infiltration and thus would confound our survival data. We believe that there's worse survival in these patients with increased CD3 infiltration due to the fact that their tumors are likely more aggressive and inflammatory and thus would result in worse outcomes. In addition, as I previously showed, a significant portion of these cells are actually immunosuppressive Tregs. We also examined the PD-1 and found that increased PD-1 expression within the tumor was associated with worse outcomes. This is likely due to the increased T cell exhaustion in these tumors. However, given the significant amount of T cells present, these data suggest that immunomodulators could still play a role in the treatment of these meningiomas by converting these lymphocytes to a more pro-inflammatory state. So, to summarize, with regards to tumor PD-L1, similar to previously published reports, we found that meningiomas did express PD-L1 on the tumor cells and that it was primarily, it was higher in higher grade tumors. What's novel about our study is we also looked at the immune profile on the periphery, and we found that peripheral myeloid PD-L1 and peripheral MDSCs were expanded in grade three meningiomas. Unfortunately, neither intratumoral nor peripheral markers of immunosuppression were significantly associated with outcome. However, the utility of our findings is that peripheral myeloid PD-L1 can be used as a predictive biomarker for grade three tumors with a positive predictive value in excess of 90%. And then lastly, we demonstrated that meningiomas had a significant amount of T cell infiltration and that a significant portion of these T cells were PD-1 positive T cells or immunosuppressive Tregs. Therefore, we believe our data still supports the use of immune checkpoint inhibitors in high degree meningiomas with the overall goal of converting these lymphocytes to a more pro-inflammatory phenotype. I would like to thank Dr. Block and the rest of the lab, as well as Dr. Horbinski, who runs the Brain Tumor Bank at Northwestern University. I'd also like to thank the Howard Hughes Medical Institute for funding this research through the Medical Fellows Program. Thank you for your time.

systemic immunosuppression

local immunosuppression

high-grade meningiomas

immunotherapy

immune checkpoints