Immunotherapy reverses glioma-driven dysfunction of immune system homeostasis.

BACKGROUND: Glioma-induced immune dysregulation of the hematopoietic system has been described in a limited number of studies. In this study, our group further demonstrates that gliomas interrupt the cellular differentiation programming and outcomes of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. HSPCs from glioma-bearing mice are reprogrammed and driven towards expansion of myeloid lineage precursors and myeloid-derived suppressor cells (MDSCs) in secondary lymphoid organs. However, we found this expansion is reversed by immunotherapy. Adoptive cellular therapy (ACT) has been demonstrably efficacious in multiple preclinical models of central nervous system (CNS) malignancies, and here we describe how glioma-induced dysfunction is reversed by this immunotherapeutic platform. METHODS: The impact of orthotopic KR158B-luc glioma on HSPCs was evaluated in an unbiased fashion using single cell RNAseq (scRNAseq) of lineage- cells and phenotypically using flow cytometry. Mature myeloid cell frequencies and function were also evaluated using flow cytometry. Finally, ACT containing total body irradiation, tumor RNA-pulsed dendritic cells, tumor-reactive T cells and HSPCs isolated from glioma-bearing or non-tumor-bearing mice were used to evaluate cell fate differentiation and survival. RESULTS: Using scRNAseq, we observed an altered HSPC landscape in glioma-bearing versus non-tumor-bearing mice . In addition, an expansion of myeloid lineage subsets, including granulocyte macrophage precursors (GMPs) and MDSCs, were observed in glioma-bearing mice relative to non-tumor-bearing controls. Furthermore, MDSCs from glioma-bearing mice demonstrated increased suppressive capacity toward tumor-specific T cells as compared with MDSCs from non-tumor-bearing hosts. Interestingly, treatment with ACT overcame these suppressive properties. When HSPCs from glioma-bearing mice were transferred in the context of ACT, we observed significant survival benefit and long-term cures in orthotopic glioma models compared with mice treated with ACT using non-glioma-bearing HSPCs.

Are State-Level HIV Testing Policies for Minors Associated With HIV Testing Behavior and Awareness of Home-Based HIV Testing in Young Men Who Have Sex With Men?

PURPOSE: The objective of this study was to determine whether state-level policies that restrict minors' access to confidential HIV testing without parental consent may suppress HIV testing in young men who have sex with men (YMSM) in the United States. METHODS: Secondary data from a national HIV prevention trial among YMSM aged 13-17 years (N= 612) were analyzed to evaluate the association between living in a state with restrictive HIV testing policies for minors and HIV testing behavior, awareness of home-based HIV testing, and confidential interactions with a physician. Multilevel logistic regression models were adjusted for age, parents' education level, race, ethnicity, sexual orientation, being sexually experienced, and health literacy of medical forms and controlled for clustering by state. Age-stratified models by state-level age of consent for HIV testing and a subanalysis (including only sexually experienced participants) were also conducted. RESULTS: Residing in a state with restrictive HIV testing policies was associated with the lack of awareness of home-based HIV testing (adjusted odds ratio [aOR]: 3.06; 95% confidence intervals [CI]: 1.49, 6.28). No significant associations were found for HIV testing behavior (aOR: 1.81; 95% CI: 0.85, 3.84), speaking privately with a physician (aOR: 1.00; 95% CI: 0.56, 1.79), or discussing confidentiality with a physician (aOR: 0.95; 95% CI: 0.52, 1.71) and HIV testing policies for minors. These results were consistent in both the age-stratified models and subanalysis. DISCUSSION: HIV testing proportions among YMSM did not differ by state-level minor consent laws. However, YMSM living in states with restrictive policies on HIV testing for minors were less likely to be aware of home-based HIV testing.

Immune Escape After Adoptive T-cell Therapy for Malignant Gliomas.

PURPOSE: Immunotherapy has been demonstrably effective against multiple cancers, yet tumor escape is common. It remains unclear how brain tumors escape immunotherapy and how to overcome this immune escape. EXPERIMENTAL DESIGN: We studied KR158B-luc glioma-bearing mice during treatment with adoptive cellular therapy (ACT) with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T-cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. In addition, programmed cell death protein-1 (PD-1) checkpoint blockade was studied in combination with ACT. RESULTS: Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of MHC class I, and upregulation of checkpoint molecules. Polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60%. The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon natural killer cells and T cells. CONCLUSIONS: These findings suggest that the immune landscape of brain tumors are markedly different postimmunotherapy yet can still be targeted with immunotherapy.