Reshuffling the Deck to Overcome Anti-PD-1 Therapeutic Resistance
Although melanoma patients can derive durable benefit from anti-PD-1 therapy, primary resistance to anti-PD-1 therapy remains a significant issue and is associated with distinct gut microbiota. Davar and colleagues have demonstrated that fecal microbiota transplant (FMT) from long-term responders may overcome anti-PD-1 therapeutic resistance. A single FMT was performed in 15 primary anti-PD-1 refractory patients in combination with pembrolizumab treatment and 6/15 patient had durable disease control over a year, including three partial responses. Response was associated with a shift toward the donor microbiome with IgG response, increased CD56+CD8+ T-cell activation and mucosal-associated invariant T cells, and decreased IL8-producing myeloid cells.
Expert Commentary: This study suggests that FMT can reverse an immunosuppressive tumor microenvironment and overcome anti-PD-L1 resistance.
Targeting Stem Cells in Sarcoma
Using a genome-wide CRISPR screening approach, Wang and colleagues identified Kruppel-like factor 11 (KLF11) as a critical negative regulator of osteosarcoma cancer stem cells. Epigenetic silencing of KLF11 in osteosarcoma leads to sustained activation of YAP signaling by acting as a transcriptional repressor of a subset of YAP target genes. They propose that this provides a potential druggable pathway that could be exploited for the treatment of osteosarcoma: pharmacological activation of KLF11 resulting from demethylation of its promoter restored response to chemotherapy and provided durable responses in vivo.
Expert Commentary: The authors suggest that KLF11 may play a role in the regulation of cancer stem cells in soft tissue sarcomas that is worthy of further investigation, as these are aggressive tumors with limited treatment options.
TORC1/2 Kinase, Metabolism, and MYC-Driven Medulloblastoma
Patients with group 3 medulloblastoma show high levels of MYC, activation of mTOR, and survival of less than 50%. Maynard and colleagues treated medulloblastoma group 3 cell lines with the mTOR kinase inhibitor sapanisertib and observed a decrease in proliferation and an induction of apoptosis. In addition, they performed a metabolic profiling in MYC-amplified medulloblastoma orthotopic xenografts, detecting increased glutathione levels and glutathione pathway components. After treatment, glutathione production was significantly reduced. As glutathione detoxifies platinum chemotherapy agents, they combined sapinisertib with carboplatin. This combination impaired cell viability and resulted in an extended survival of mice with medulloblastoma orthotopic xenografts at clinically relevant doses.
Expert Commentary: Maynard and colleagues demonstrated the key role of glutathione in platinum therapy resistance. Targeting glutathione with TORC1/2 inhibitors in combination with platinum-containing drugs is a promising therapeutic strategy for high-risk medulloblastoma patients.
Taking the Fat Out of Cancer Suppresses CD8 T-cell Function
Ringel and colleagues showed that a high fat content diet (HFD) disrupts antitumor immune responses, driving cancer progression. In mouse models, HFD increased fatty acid oxidation. This metabolic switch was caused by transcriptional downregulation of prolyl hydroxylase-3 (Phd3) in tumor cells, which increased transport of acyl-CoA from the cytosol into the mitochondria to support fatty acid oxidation. This metabolic shift reduced free fatty acids specifically within the tumor microenvironment, depriving CD8+ T cells of free fatty acids required for their local activation, proliferation, and function. Overexpression of Phd3 in tumor cells restored T-cell function and improved disease control in mice with an HFD. In patients with colorectal cancer, a strong correlation was found between high body mass index and reduced expression of PHD3 and reduced infiltration of CD8+ T cells into tumors.
Expert Commentary: Diets high in fat cause tumor cells to shift metabolism to fatty acid oxidation that deprives CD8+ T cells of free fatty acids required for their antitumor activities.
Proteogenomic and Metabolomic Landscape of Glioblastoma
Wang and colleagues integrated analyses of mass spectrometry-based proteome, phosphoproteome, acetylome, metabolome, lipidome, and single-cell transcriptomics on 99 treatment-naïve glioblastoma tumors. They demonstrated insights into the immune landscape, cell specific signatures, histone acetylation, and the presence of signaling hubs, which could provide therapeutic targets. The authors identified four immune subtypes characterized by differing abundance of microglia, macrophages, and lymphocytes. They further found DNA repair pathways in p53-mutated tumors and a phospho-signaling signature in receptor tyrosine kinase-altered tumors, as well as an enrichment of H2B acetylation in classical-like glioblastoma with low macrophage content. Furthermore, they showed that the mesenchymal EMT signature was specific to tumor but not stromal cells.
Expert Commentary: The data presented give insights to new stratifications of glioblastoma patients for precision medicine.
Relaxin the Fibrotic Tumor Microenvironment
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic environment that contributes to the lack of efficacious treatments for this aggressive disease. Zhou and colleagues demonstrated that the systemic hormone relaxin can decrease tumor-associated fibrosis and increase T-cell infiltration following its targeted delivery in a mouse model of PDAC. They showed that RXFP1, the primary relaxin receptor, was predominantly expressed on macrophages within the tumor microenvironment and that the anti-fibrotic activity of relaxin was dependent on F4/80+CD206+ macrophages. Relaxin synergized with immune checkpoint blockade by increasing phagocytic activity of this subset of macrophages and enhancing T-cell-mediated tumor cell killing.
Expert Commentary: This study provides further evidence that targeting macrophages within the tumor-microenvironment can provide alternative treatment strategies in highly desmoplastic tumors when combined with immune checkpoint inhibitors.
Zhou X, Liu Y, Hu M, Wang M, Liu X, Huang L. Relaxin gene delivery modulates macrophages to resolve cancer fibrosis and synergizes with immune checkpoint blockade therapy. Sci Adv 2021; 7:eabb6596. DOI: 10.1126/sciadv.abb6596.
Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.