Ibrutinib‐based combination therapy with high‐dose methotrexate (HD‐MTX) has recently shown clinical activity against relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL). Herein, we report our real‐world experience of treating 11 newly diagnosed PCNSL patients with the ibrutinib/MTX combination. HD‐MTX was given at 3.5 g/m² every 2‐week for eight doses. Ibrutinib was held upon HD‐MTX infusion until clearance and was administered daily post‐induction until disease progression, intolerable toxicity, or death. Nine out of 11 patients completed the induction phase and received ibrutinib as maintenance therapy. An objective response rate (ORR) of 82% (9/11) was observed including complete response (64%) and partial response (18%). The median progression‐free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The ibrutinib/MTX combination was well tolerated in these treatment‐naïve PCNSL patients with an acceptable safety profile. Moreover, the longitudinal analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) revealed that CSF ctDNA detection was closely associated with tumor response, and sustained tumor responses correlated with the clearance of ctDNA from the CSF. In sum, our data not only demonstrated the clinical benefit of the ibrutinib and HD‐MTX combination regimen in treating newly diagnosed PCNSL patients in a real‐world setting, but also highlighted the significance of liquid biopsy including CSF ctDNA in tracing tumor burden and assessing treatment response.

The use of vaccines for cancer therapy is a promising immunotherapeutic strategy that has been shown to be effective against various cancers. Vaccines directly target tumors but their efficacy against glioblastoma multiforme (GBM) remains unclear. Immunotyping that classifies tumor samples is considered to be a biomarker for immunotherapy. This study aimed to identify potential GBM antigens suitable for vaccine development and develop a tool to predict the response of GBM patients to vaccination based on the immunotype. Gene Expression Profiling Interactive Analysis (GEPIA) was applied to evaluate the expression profile of GBM antigens and their influence on clinical prognosis, while the cBioPortal program was utilized to integrate and analyze genetic alterations. The correlation between antigens and antigen processing cells was assessed using TIMER. RNA-seq data of GBM samples and their corresponding clinical data were downloaded from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) for further clustering analysis. Six overexpressed and mutated tumor antigens (ARHGAP9, ARHGAP30, CLEC7A, MAN2B1, ARPC1B and PLB1) were highly correlated with the survival rate of GBM patients and the infiltration of antigen presenting cells in GBMs. With distinct cellular and molecular characteristics, three immune subtypes (IS1-IS3) of GBMs were identified and GBMs from IS3 subtype were more likely to benefit from vaccination. Through graph learning-based dimensional reduction, immune landscape was depicted and revealed the existence of heterogeneity among individual GBM patients. Finally, WGCNA can identify potential vaccination biomarkers by clustering immune related genes. In summary, the six tumor antigens are potential targets for developing anti-GBMs mRNA vaccine, and the immunotypes can be used for evaluating vaccination response.

Brain metastases (BrMs) are the leading cause of death in patients with solid cancers. BrMs exhibit a highly immunosuppressive milieu and poor response to immunotherapies; however, the underlying mechanism remains largely unclear. Here, we show that upregulation of HSP47 in tumor cells drives metastatic colonization and outgrowth in the brain by creating an immunosuppressive microenvironment. HSP47-mediated collagen deposition in the metastatic niche promotes microglial polarization to the M2 phenotype via the α2β1 integrin/nuclear factor κB pathway, which upregulates the anti-inflammatory cytokines and represses CD8⁺ T cell anti-tumor responses. Depletion of microglia reverses HSP47-induced inactivation of CD8⁺ T cells and abolishes BrM. Col003, an inhibitor disrupting HSP47-collagen association restores an anti-tumor immunity and enhances the efficacy of anti-PD-L1 immunotherapy in BrM-bearing mice. Our study supports that HSP47 is a critical determinant of M2 microglial polarization and immunosuppression and that blocking the HSP47-collagen axis represents a promising therapeutic strategy against brain metastatic tumors.

Background: The effectiveness of PD-1/PD-L1 immune checkpoint blockade therapy in glioblastoma (GBM) is limited due to the tumor immunosuppressive microenvironment (TIME). Therefore, strategies of reprogramming TIME to a pro-inflammatory state offer a promising therapeutic approach. Methods: We applied bioinformatics analysis of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (stRNA-seq) to identify a significant accumulation of cancer-associated fibroblasts (CAFs) subclusters with elevated LRRC15 expression in the nonresponders to anti-PD-1 therapy. The molecular mechanism of LRRC15 was functionally validated in vitro and in vivo. Results: These CAFs subclusters drive the infiltration of macrophages (Mφ) into the tumor microenvironment and promote their polarization toward the M2 phenotype. Deletion of Lrrc15 in CAFs significantly restrained tumor growth and prolonged survival in mouse models. Mechanistically, LRRC15 in CAFs promotes IL8 expression by activating the downstream FAK/SRC/NF-κB pathways, leading to Mφ migration and M2-like polarization. In turn, M2-like Mφs secrete TGF-β, which induces LRRC15 expression in CAFs via SMAD2-dependent transcriptional activation. Targeting CAFs subcluster with elevated LRRC15 expression in combination with anti-PD-1 treatment enhanced antitumor efficacy. Conclusions: Our findings suggest that targeting LRRC15 may provide a novel strategy to augment anti-PD-1 therapy and overcome immunotherapy resistance in GBM.

Background: Intracerebral hemorrhage (ICH) is a common neurological crisis leading to high mortality and morbidity. Oxidative stress-induced secondary injury plays a critical role in neurological deterioration. Previously, we synthesized a porous [email protected]₂ nanocomposite and identified their therapeutic role in osteonecrosis of the femoral head. Whether this nanocomposite is neuroprotective remains to be elucidated. Methods: A porous [email protected]₂ nanocomposite was synthesized, and its biosafety was determined using a CCK-8 assay. The neuroprotective effect was evaluated by TUNEL staining, and intracellular ROS were detected with a DCFH-DA probe in SH-SY5Y cells exposed to hemin. Furthermore, the effect of the nanocomposite on cell apoptosis, brain edema and blood–brain barrier permeability were evaluated in a collagenase-induced ICH mouse model. The potential mechanism was also explored. Results: The results demonstrated that [email protected]₂ treatment significantly improved neurological function, increased glutathione peroxidase activity and downregulated malonaldehyde levels. The proportion of apoptotic cells, brain edema and blood–brain barrier permeability were reduced significantly in ICH mice treated with [email protected]₂ compared to vehicle-treated mice. In vitro, [email protected]₂ protected SH-SY5Y cells from hemin-induced apoptosis by preventing intracellular reactive oxygen species accumulation. Conclusion: These results suggested that the porous [email protected]₂ nanocomposite exerted neuroprotection by suppressing oxidative stress. [email protected]₂ may be a potential candidate for the clinical treatment of ICH and oxidative stress-related brain injuries.