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Immunotherapy has revolutionized patient care, however, the majority of patients with cancer still do not benefit from this treatment modality. This is due to many factors, including a complex tumor microenvironment (TME) that has too few functional effector cells and/or the presence of many inhibitory cells. Understanding how to remodel the TME to potentiate productive immunity against cancer cells is an active area of research. Growth and Differentiation Factor 15 (GDF-15) is a member of the TGF-beta superfamily that is overexpressed by many solid tumors and is implicated in dampening immune responses. The present study was aimed at understanding the role of GDF-15 in tumor immune biology. We show that GDF-15 can inhibit the differentiation and activation of human monocyte-derived dendritic cells (DCs) and prevent T cell activation. Furthermore blockade of GDF-15 by AZD8853, an anti-GDF15 monoclonal antibody, can restore these activities in vitro. Tumors derived from GDF15 knock-out syngeneic cell lines, Renca and MC-38, show 2-3 fold increases in T cells and activated DCs in the TME as compared to tumors derived from isogeneic parental cells. Treatment of mice with anti-GDF15 mAb leads to substantial anti-tumor activity in anti-PD-L1 refractory LL/2 and MBT2 syngeneic tumors with 50% of the animals showing complete tumor regressions. Coupled with this anti-tumor activity, we show that after 2 doses of anti-GDF15 mAb there is an increase in both activated T cells and DCs in the TME. Depletion of T cells, using anti-CD4 and anti-CD8, in mice ablates the anti-tumor activity observed with anti-GDF15 mAb treatment. These results suggest that inhibition of GDF15 by AZD8853 may be an attractive therapeutic strategy for patients with solid tumors that have high expression of GDF15. Citation Format: Elaine Hurt, Suneetha Thomas, Kathy Mulgrew, Stephen Blackmore, James Moynihan, Fiona Cusdin, Roger Dodd, Peter Cariuk, Anna Sigurdardottir, Emily Brannigan, Claire Dobson, Rakesh Kumar, Mark Cobbold. AZD8853: A novel antibody targeting GDF15 for immunotherapy refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1828.

Giving protein folding a helping hand The reversible phosphorylation of proteins controls virtually all aspects of cell and organismal function. Targeting phosphorylation offers a broad range of therapeutic opportunities, and thus kinases have become important therapeutic targets. As targets, phosphatases should be as attractive, but in fact they are more challenging to manipulate. Das et al. have found a safe and specific inhibitor, called Sephin1, that targets a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 binds and inhibits PPP1R15A, but not the related regulatory phosphatase PPP1R15B. In mice, Sephin1 prolonged a stress-induced phospho-signaling pathway to prevent the pathological defects of the unrelated protein-misfolding diseases Charcot-Marie-Tooth 1B and amyotrophic lateral sclerosis. Science , this issue p. 239

Summary Protein phosphorylation is a prevalent and ubiquitous mechanism of regulation. Kinases are popular drug targets, but identifying selective phosphatase inhibitors has been challenging. Here, we used surface plasmon resonance to design a method to enable target-based discovery of selective serine/threonine phosphatase inhibitors. The method targeted a regulatory subunit of protein phosphatase 1, PPP1R15B (R15B), a negative regulator of proteostasis. This yielded Raphin1, a selective inhibitor of R15B. In cells, Raphin1 caused a rapid and transient accumulation of its phosphorylated substrate, resulting in a transient attenuation of protein synthesis. In vitro, Raphin1 inhibits the recombinant R15B-PP1c holoenzyme, but not the closely related R15A-PP1c, by interfering with substrate recruitment. Raphin1 was orally bioavailable, crossed the blood-brain barrier, and demonstrated efficacy in a mouse model of Huntington’s disease. This identifies R15B as a druggable target and provides a platform for target-based discovery of inhibitors of serine/threonine phosphatases., Graphical Abstract, Highlights • A method to enable target-based discovery of selective phosphatase inhibitors • Raphin1 inhibits PPP1R15B, transiently lowers translation, and improves proteostasis • Raphin1 is orally available and crosses the blood-brain barrier • Raphin1 decreases deficits in a mouse model of Huntington’s disease, An orally available selective phosphatase inhibitor improves proteostasis and diminishes deficits in a mouse model of Huntington’s disease.

Summary The proteasome is essential for the selective degradation of most cellular proteins. To survive overwhelming demands on the proteasome arising during environmental stresses, cells increase proteasome abundance. Proteasome assembly is known to be complex. How stressed cells overcome this vital challenge is unknown. In an unbiased suppressor screen aimed at rescuing the defects of a yeast Rpt6 thermosensitive proteasome mutant, we identified a protein, hereafter named Adc17, as it functions as an ATPase dedicated chaperone. Adc17 interacts with the amino terminus of Rpt6 to assist formation of the Rpt6-Rpt3 ATPase pair, an early step in proteasome assembly. Adc17 is important for cell fitness, and its absence aggravates proteasome defects. The abundance of Adc17 increases upon proteasome stresses, and its function is crucial to maintain homeostatic proteasome levels. Thus, cells have mechanisms to adjust proteasome assembly when demands increase, and Adc17 is a critical effector of this process., Graphical Abstract, Highlights • The maintenance of adequate levels of proteasome is vital • Cells increase proteasome abundance when the needs increase • Adc17 is an inducible chaperone that adapts proteasome assembly to increased needs • Adc17 assists the pairing of Rpt6 and Rpt3, an early step in proteasome assembly, Cells increase proteasome abundance in order to survive during environmental stress. Hanssum et al. reveal a mechanism for controlling proteasome abundance, showing that Adc17 is an inducible chaperone needed for proteasome assembly during stress.