The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Commentary/editorials Section Editor, Christian Capitini, MD.
“Trans-endocytosis of intact IL-15Ralpha–IL-15 complex from presenting cells into NK cells favors signaling for proliferation” by Olga Anton et al.
The cytokine IL-15 is essential for natural killer (NK) cell proliferation and survival and it activates signaling through trans-presentation by cells expressing IL-15 bound to the alpha chain of the IL-15 receptor (IL-15Ralpha). Olga Anton and colleagues revealed that the survival- and proliferation-promoting signaling programs activated by IL-15 are separable and distinct, depending on the mode of trans-presentation. Using multiple reporters with IL-15Ralpha tagged both extracellularly and intracellularly on trans-presenting dendritic cells, Anton et al. demonstrated NK cells uptake the IL-15—IL-15Ralpha complex as both a soluble form released by shedding as well as through trans-endocytosis of an intact, membrane-associated complex. Inhibition of matrix metalloproteinases to prevent cleavage and shedding of the soluble for of the complex significantly reduced Stat5 phosphorylation, whereas silencing of a small GTPase that plays a role in trans-endocytosis impaired S6 phosphorylation. Double-membrane intracellular compartments containing IL-15Ralpha–IL-15 complexes were visible via transmission electron microscopy, supporting a trans-endocytosis mechanism where a portion of the plasma membrane of the trans-presenting dendritic cell is snatched into the NK cell endocytic vesicle. The distinct functional outcomes of different IL-15 trans-presentation pathways revealed by the study could have implications for stimulation of NK cells used in cancer immunotherapy.
“c-Jun overexpression in CAR T cells induces exhaustion resistance” by Rachel Lynn et al.
T cell exhaustion may limit the therapeutic efficacy of chimeric antigen receptor (CAR) T cells, but little is known about the mechanisms responsible for impaired function. By engineering tonic signaling T cells with a GD2-specific CD28z-containing CAR, Rachel Lynn et al. created a model that mimicked a profound exhaustion phenotype in vitro, with high expression of inhibitory receptors, reduced expansion, and decreased production of IL-2 and interferon gamma. Using the model, more than 20,000 differentially observed chromatin regions were identified in exhausted T cells and transcription factor motif enrichment analysis revealed strong enrichment for AP-1—bZIP and bZIP—IRF binding motifs. Overexpression of c-Jun rescued cytokine production in the exhausted CAR T cell model and enhanced long-term proliferation in CAR T cells without tonic signaling. Transcriptional activation by c-Jun was dispensable for overcoming exhaustion in the tonic signaling model, while mutant c-Jun deficient in chromatin binding or dimerization did not rescue cytokine production. In several different mouse models, overexpression of cJun enhanced the anti-tumor activity of CAR T cells, promoted expansion and cytokine production, and decreased hallmarks of exhaustion including PD-1 expression. The results support a model whereby cJun disrupts or displaces AP-1j-IRF complexes to alleviate expression of exhaustion-associated genes, raising the prospect of clinically testing JUN CAR T cells with enhanced ant-tumor efficacy.
“The therapeutic landscape for cells engineered with chimeric antigen receptors” by Matthew MacKay et al.
Analyzing clinicaltrials.gov, Matthew MacKay and colleagues identified more than 520 CAR clinical trials, of which 501 were nonwithdrawn interventional cancer treatments encompassing 64 unique CARs across a variety of targets and disease states. To comprehensively characterize promising targets and potential safety concerns, all current CAR targets were annotated with expression data from both normal and cancer tissue from the Human Protein Atlas (HPA). Based on expression patterns in healthy and tumor tissues, existing CAR targets were evaluated for the likelihood of on-target/off-tumor toxicity. New potential targets were also predicted, including 2 that have recently been tested in pre-clinical models. As a resource for physicians, researchers and patients interested in CAR trials and applications, the annotation and analysis including key aspects of CAR trials that are typically either absent or difficult to access from the clinicaltrials.gov registry, such as the co-stimulatory domain in the engineered receptor, purity of the infusion product or integration of the construct, are all available at a new dynamic online repository, https://carglobaltrials.com.
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