Quarterly picks from the editors

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Science Translational Medicine  25 Mar 2020:
Vol. 12, Issue 536, eabb4950
DOI: 10.1126/scitranslmed.abb4950


Four times a year, the Science Translational Medicine editors select recently published articles across the Science family of journals and highlight interesting translational ties. These short write-ups identify common links between disparate diseases; technologies and research approaches that could prove complementary; and biomedical insights that may inform therapies or treatments. This quarter’s articles cover cytokine-based therapies, GLP-1 receptors in metabolic disease, oncoproteins and checkpoint blockade, imaging insights into subcellular structures, engineered T cell treatments, and kidney transplant rejection.


GLP-1 receptors: Location, location, location

Glucagon-like peptide-1 (GLP-1) is a hormone of therapeutic interest for its multiple actions on food consumption and glucose homeostasis. Receptors for this hormone are found in both the nervous system and pancreas. Ackeifi et al. showed that combining any GLP-1 receptor agonist with any DYRK1A inhibitor induced synergistic and relatively specific proliferation of functional human pancreatic β cells, suggesting the potential utility of this combination in diabetes driven by β cell deficiency. In a separate paper, Fortin et al. demonstrated that a subset of GLP-1 receptors in the hindbrain of rats helped centrally mediate appetite suppression and weight loss by liraglutide, a medication commonly prescribed to patients with type 2 diabetes or obesity. These studies illustrate how GLP-1 receptors in different tissues can produce different therapeutic effects on metabolism. —CAC


Structural insights

Microscopy provides insight into life at the subcellular scale. Hoffman et al. report an imaging workflow that maps the spatial compartmentalization of proteins and organelles within different cells, allowing them to study structures such as microtubules that form the cytoskeleton and cilia, protrusions that extend from the surface of cells. Le Guennec et al. also studied microtubules but used cryo–electron tomography and ultrastructure expansion microscopy to determine how proteins bind to stabilize centrioles, another structure involved in cilia formation. Liu et al. demonstrate how imaging can be applied to ciliopathies to map protein mislocalization, identify structural and functional defects, and complement existing methods to diagnose primary ciliary dyskinesia. Together, these papers illustrate how imaging can reveal links between structure and function. —CC


A multifrontal attack to conquer PD-1

Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is a promising therapeutic approach for treating cancers. However, PD-1 blockade seems to be effective only in a fraction of patients. In four recent papers, scientists studied multiple facets of PD-1. Marasco et al. elucidated the structural biology behind PD-1–mediated T cell inactivation. Strauss et al. reported that PD-1 expressed in myeloid cells contributes to the antitumor effect of PD-1 blockade, whereas Wang et al. showed that PD-1 blockade in sensory neurons impaired the antinociceptive effects of opioids. Lastly, Xiao et al. developed a combination nanotherapy targeting PD-1 and the transcription factor nuclear factor κB that was effective in a mouse model of melanoma resistant to PD-1 blockade. These results highlight the complex biology of PD-1. —MM


Rejecting kidney transplant rejection

One of the challenges of kidney transplantation is avoiding rejection of the donor kidney while minimizing immunosuppressive drugs, which have extensive side effects. Busque et al. found that transplanting hematopoietic cells and a kidney from the same donor resulted in persistent mixed chimerism in fully human leukocyte antigen– or haplotype-matched recipients, and this mixed chimerism allowed for at least partial immunosuppressive drug withdrawal without development of rejection. Speaking of rejection, what is the best way to test for it? Traditional monitoring involves measurement of serum creatinine and invasive kidney biopsies, but Yang et al. have presented a new way to diagnose rejection using a quantitative urine score. This score, which measures urine DNA, proteins, and metabolites, can diagnose acute rejection even in the absence of elevated serum creatinine and can prevent unnecessary biopsies. These findings highlight ongoing efforts to detect and avoid kidney transplant rejection. —MN


Of MYCs and men

Although the MYC family of oncogenes—including MYCN—is well known to play a role in a variety of cancers, the full extent of its involvement is not yet understood, and there are no drugs that can target these oncogenes directly. In two recent papers, Guo et al. and Schafer et al. investigated the involvement of MYCN and potential therapeutic targeting approaches in two different cancer types. Guo et al. delineated a feedback loop involving MYCN in neuroblastoma, which could be interrupted by inhibiting a protein that interacts with MYCN. Schafer et al. reported MYCN overexpression in triple-negative breast cancer, a tumor type in which MYCN was not previously known to play a role, and identified a two-drug combination for targeting it in this context. These studies expand our understanding of MYCN function and suggest that this pathway may be targetable after all. —YN


Small but mighty

Immune responses are orchestrated in part by small soluble mediators, such as cytokines. Three recent papers leverage cytokine signaling to treat different diseases. Unlike other therapies that dampen immune responses, Mack et al. suggest that activating natural killer cells through interleukin-15 could be useful for treating atopic dermatitis. To better invigorate T cells to fight tumors, Nakao et al. added cytokines to an oncolytic virus, which showed efficacy in difficult-to-treat cancer models when combined with checkpoint blockade. Last, Li et al. developed an anti–interleukin-1β therapy with platelet microparticles, which might be safer than systemic therapy for acute myocardial infarction. Cytokine-based therapies such as these have the potential to steer immune responses for patient benefit. —LP


Deadly engineered T cells stalk tumors

A promising approach to treating tumors refractory to chemotherapy is to reinfuse patients with their own T cells engineered ex vivo to express altered T cell receptors (TCRs) with enhanced tumor-killing capacity. Two recent papers take different approaches to boosting the tumor-killing activity of engineered T cells still further. In a first-in-human phase I clinical trial, Stadtmauer et al. applied the power of CRISPR-Cas9 gene editing to excise the normal TCRs of T cells from three patients with refractory cancer; they replaced these TCRs with synthetic, cancer-specific TCRs and also deleted PD-1, an immune checkpoint molecule that interferes with T cell activity. When reinfused into the three patients, the engineered T cells engrafted and survived for nine months without side effects. Meanwhile, Wang et al. engineered T cells to express chlorotoxin, a short peptide from the death stalker scorpion that selectively targeted tumor cells when infused into mice bearing human glioblastoma xenografts. Both papers showcase strategies for genetically tinkering with T cells to boost their tumor-killing activity, with potential benefits for patients who have failed traditional chemotherapy. —OS

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