Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer
Mutated, activated KRAS is a common feature of pancreatic ductal adenocarcinoma (PDAC). Inhibitors of the downstream MEK and CDK4/6 pathways suppress PDAC growth by inducing cellular senescence and production of chemokines, cytokines, and matrix metalloproteinases. This triggers vasculature remodeling of the PDAC tumors and subsequent NF-κB– and VEGFR-driven tumor infiltration by CD8+ T cells. MEK and CDK4/6 inhibitors lead to exhaustion of the recruited T cells, which are rescued by PD-1 blockade. Inducing senescence with immune checkpoint blockade may improve outcomes.
Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling
Radiation induces genomic DNA (gDNA) fragmentation but little cytosolic DNA sensing with IFN-I production. Radiation also induces mitochondrial permeabilization, and the mitochondrial DNA (mtDNA) activates caspase-9, leading to intrinsic apoptosis. By disrupting caspase-9, apoptosis is inhibited and the cytosolic mtDNA activates the STING pathway and increases IFN-I, promoting cross-priming by DCs and activating T cells. However, the T cells become exhausted, and combining PD-L1 blockade with radiation therapy and caspase inhibition increases antitumor activity and abscopal effects.
Pooled knockin targeting for genome engineering of cellular immunotherapies
Adoptive cell therapies (ACT) have had limited success in solid tumors. The authors develop pooled knock-in sequencing (PoKI-seq), a high-throughput barcoding method in which pooled, targeted, knock-in constructs in T cells are assessed via combined single-cell transcriptome analysis and pooled knock-in screening, as a strategy to identify constructs that can improve T-cell abundance and function for treating solid tumors. Among a large panel of natural and synthetic genes, knock-in of a synthetic TGFβR2-41BB chimeric receptor was found to best improve in vitro activity and efficacy of ACT in melanoma.
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
Pancreatic ductal adenocarcinoma (PDAC) rarely responds to immune checkpoint blockade (ICB). Although MHC-I is downregulated in PDAC, it is not due to mutations in, or loss of heterozygosity of, antigen presentation or structural genes. Instead, surface MHC-I is selectively targeted by lysosomes via NBR1-mediated autophagy. Autophagy inhibition restores MHC-I expression and improves antitumor immunity, effects dependent on CD8+ T cells and enhanced by concurrent dual ICB. This autophagy-mediated immune evasion mechanism in PDAC cells suggests that its targeting could boost antitumor responses.
The governing of myeloid cells
Factors that regulate function of the heterogeneous myeloid cells in cancer are not fully known. Zhang et al. find that in patients and mice with colorectal tumors, myeloid cell–targeting immunotherapies have distinct macrophage and DC subset–specific effects, revealing myeloid cells as central players in cell interaction networks in the tumor. Mohamed et al. demonstrate that myeloid-derived suppressor cell (MDSC) function relies on PERK, the unfolded protein response–related kinase, via activation of transcription factor NRF2. PERK deletion disrupts mitochondrial homeostasis and induces IFN by activating the STING pathway, reprogramming the MDSC to promote CD8+ T-cell responses. Thus, intelligent targeting of defined myeloid cells can manipulate regulation and improve antitumor responses.
Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer
CRISPR-Cas9 is being investigated to improve immunotherapy responses. A phase I clinical trial shows that T cells with a disrupted PD-1 gene infused into patients with treatment-refractory non–small cell lung cancer had only grade 1/2 treatment-related adverse events. The edited T cells persist post-infusion and are trackable. Off-target mutation frequency was 0.05%. These data support the safety and feasibility of clinical use in T cell–based immunotherapies.