(i) KaplanCMeier estimates of progression-free survival by PD1 positivity in all meningiomas. T-cells infiltration and PD-1 expression are independently associated with outcome In univariate analysis, we found CD3 infiltration into the tumor to be a significant predictor of PFS in grade II and III meningioma patients (p=0.031, Figure 4H). was not associated with progression-free survival. High grade meningiomas had increased T-cell infiltration. However, a significant proportion of these T-cells were exhausted PD1+ T-cells and immunosuppressive Tregs. Conclusions: Patients with meningiomas exhibit signs of peripheral immunosuppression, including increased PD-L1 on myeloid cells and elevated MDSC abundance proportional to tumor grade. Additionally, the tumors express substantial PD-L1 proportional to tumor grade. These results suggest a role for immune checkpoint inhibitors targeting the PD-L1/PD-1 pathway in combination with standard therapies for the treatment of high-grade meningiomas. test or ANOVA. The Kaplan-Meier method was used to estimate survival distributions. Censored patients are indicated by vertical ticks on the survival plots. Differences in length of follow-up and censorship are accounted for in the Kaplan-Meier analysis, and the log-rank test remains significant where indicated by p<0.05. P-values <0.05 were considered statistically significant. Results Patients Fifty-three patients meeting the inclusion criteria were identified in our cohort. The median age at surgery was 61 years (range 25C85) and 34 patients (64%) were female. Eighteen patients had grade I, 25 patients PSI-6206 13CD3 had grade II, and 10 patients had grade III meningiomas. Of the 53 patients, thirteen (25%) had recurrent tumors and 10 patients (19%) had radiation therapy in the past. Thirty-six patients (68%) had gross total resections and the other 17 (32%) had subtotal resections. Table 1 summarizes the patients characteristics and prior therapies. Table 1: Clinical characteristics of patients included in this study.
Age at surgery, median (range)61(25C85)Sex?Female3464.2?Male1935.8WHO grade?I1834.0?II2547.2?III1018.8Karnofsky performance status?90+611.3?8000?7023.8?<7000?Unknown4584.9Ki67/MIB1 status?1C4.9%1935.8?5C10%1528.3?>10%1834.0?Unknown11.9Prior radiotherapy?Yes1018.9?No4381.1Recurrence status?Recurrent tumor1324.5?Newly diagnosed tumor4075.5Extent of resection?Gross total resection3667.9?Subtotal resection1732.1 Open in a separate window Peripheral immunosuppression in high grade meningioma patients Monocyte PD-L1 (CD45+CD11b+PD-L1+), MDSC abundance (CD33+CD11b+HLA-DRlow), and regulatory T cell (Treg) abundance (CD3+CD4+CD25+FoxP3+) were examined for each patient via flow cytometry. Higher monocyte PD-L1 was seen in patients with grade III meningiomas; mean 6.9% for grade I, 5.6% for grade II, and 12.6% for grade III meningioma patients (ANOVA, p=0.0002, Figure 1A,?,B).B). PSI-6206 13CD3 The MDSC population was greater in patients with grade II and grade III meningiomas; mean 6.4% for grade I, 13.8% for grade II, and 14.4% for grade III meningioma patients (ANOVA, p=0.023, Figure 1C,?,D).D). Across all grades, PSI-6206 13CD3 the mean percentage of Tregs among CD4+ cells was 5.2%. There was no difference in Treg abundance based on the grade of tumor (Figure 1E,?,FF). Open in a separate window Figure 1: Peripheral immune profiling of patients with meningiomas.(a) Representative gating scheme for identification of myeloid cells from peripheral blood leukocytes by flow cytometry. Live cells were gated using forward and side scatter from the total population (left), followed by identification of single cells (left-center), gating for total myeloid population of CD45+/CD11b+ cells (right-center), and gating for PD-L1+ cells (right). (b) Summary of PD-L1 expression in monocytes from each of the 53 evaluated patients as well as healthy controls ordered by percent positive expression within each grade. Patients with grade III meningiomas had significantly elevated monocyte PD-L1 compared to patients with lower grade tumors (* p < 0.05). Patients with monocyte PD-L1 expression greater than 10% are colored in red. (c) Representative gating scheme for identification of MDSCs from peripheral blood leukocytes by flow cytometry. Monocytes were gated from the total population (left), followed by identification of single cells (not shown), gating for total myeloid population of CD33+/CD11b+ Kdr cells (center), and gating for MDSCs.