A Sampling of Highlights from the Literature

Abstract

Prostaglandin E2 (from WikiMedia Commons)Neutrophils can be immunosuppressive when located in the microenvironment of tumors. GM-CSF in the tumor microenvironment stimulates STAT5-upregulation of fatty-acid transporter protein FATP2 primarily on tumor neutrophils. This increases arachidonic acid uptake and the generation of PGE2, with subsequent suppression of tumor-specific T-cell responses. By combining inhibition of FATP2 with blockade of CTLA-4, tumor growth can be effectively inhibited in two mouse tumor models.Veglia F, …, Gabrilovich DI. Nature 2019 Apr 17;569:73–8.Neo open reading frame peptides (from Koster et al., Fig. 2)Cancer cell genomes can contain frameshift mutations, from which long neopeptides can be translated. Examination of over 10,000 TGCA tumor samples finds 143,444 frame-shift mutations, and 70,000 unique peptides ≥ 10 amino acids. Tumor-drivers are commonly frame-shifted genes. The neo-open-reading-frame peptides (NOPs) converge on common peptide sequences, in that by including only 6 driver genes, 1244 new peptides could be found in 30% of the patients. NOPs offer a new source of commonly shared potential neoantigens that could inform production of an “off-the-shelf” library of vaccine reagents.Koster J and Plasterk RHA. Sci Rep 2019 Apr 29;9:6577.Antibody binding sites on PD-1 (from Fenwick et al., Fig. 2F)Clinically useful mAbs to PD-1 block the PD-L1 binding site and thereby block the inhibition signal. Fenwick and colleagues find two new mAbs that bind to PD-1, but structural analysis indicates that binding is on locations away from the PD-1 binding site. The nonblocking mAbs act through the CD28 coreceptor, restoring signaling through the AKT–NF-κB pathway, and helping further rescue exhausted T cells. Combining both types of antibodies in tumor models enhances tumor clearance over monotherapy.Fenwick C, …, Pantaleo G. J Exp Med 2019 May 23. DOI: 10.1084/jem.20182359.Effects of DDR and PD-L1 inhibition (from Sen et al., Fig. 7E)Immune checkpoint blockade is successful only in some cases of small cell lung cancer (SCLC). Sen et al. find that FDA-approved small molecule inhibitors of CHK1 and PARP, which participate in the DNA damage response, can enhance PD-L1 blockade of the CD8+ T cell antitumor response. This is mediated in part through activation of the STING pathway that leads to increased production of T cell chemoattractants like CXCL10 and CCL5. The results suggest dual therapy could improve immunotherapy in SCLC.Sen T, …, Byers LA. Cancer Discov 2019 May 1;9:646–61.Melanoma-associated lymph node (from Broggi et al., Fig. 6A)Two papers show the promise of using tumor-draining lymph node exudate as the substrate for tumor biomarkers and evaluation of antitumor immune responses. Garcia-Silva et al. make use of extracellular vesicles (EVs) to detect markers of melanoma progression and the status of BRAF mutations. Broggi et al. compare plasma to draining lymph node exudate and find the exudate and EVs to be enriched in metastatic tumor–derived factors with protein signatures that can differentiate early from advanced metastasis and provide insights into tumor interactions with the immune system.García-Silva S, …, Peinado H. J Exp Med 2019 MAY 6;216: 1061–70.Broggi MAS, …, Swartz MA. J Exp Med 2019 May 6;216:1091–107.Moderately differentiated gastric tumor (by Nephron via Wikimedia Commons)The ramifications of PD-1 blockade on regulatory T cells (Tregs) are not clear. Almost 10% of patients with gastric cancer treated with anti–PD-1 respond with rapid progression of their tumors. In these patients, treatment increases the proliferative rate and immune suppressive activity of their Tregs. Tregs from PD-1–deficient mice lack PD-1 and both proliferate strongly and have enhanced immunosuppressive activity of antitumor responses. This association of hyperprogressive disease with PD-1 treatment suggests that Tregs be routinely monitored during checkpoint blockade therapy to identify this patient subset.Kamada T, …, Nishikawa H. Proc Natl Acad Sci U S A 2019 May 14;116:9999–10008.