What We're Reading

IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity

Multiple checkpoints (from U.S. General Accounting Office via Flickr)

Checkpoint blockade has been a successful strategy in the unleashing of specific T-cell antitumor responses. The inhibitory receptor IL1R8 is highly expressed on human NK cells and increases during NK-cell maturation and activation. Through the use of IL1R8-deficient mice, IL1R8 was found to act as a checkpoint to NK cell–mediated antitumor and antiviral protection, suggesting that its blockade during therapy could enhance NK-cell activity.

Molgora M, …, Mantovani A. Nature 2017 Oct 25. doi:10.1038/nature24293.

HLA influence on tumor evasion and mutation

MHC on DCs (from P Müller et al. Cancer Immunol Res 2014)

Which peptides are presented to T cells depends on available HLA alleles. Marty et al. found that find that recurrent tumor mutations generally contain poorly presented peptides, and if not well presented by a patient's HLA, then the probability increases that such mutations will appear in progressing tumors. McGranahan et al. developed a computational tool, LOHHLA, that uses sequencing data to measure the loss of HLA alleles in tumors. Allele loss was common in non–small cell lung cancer with high neoepitope loads and provided a mechanism for immune escape and outgrowth of mutated subclones.

Marty R, …, Carter H. Cell 2017 Oct 26. DOI: 10.1016/j.cell.2017.09.050.

McGranahan N, …, Swanton C. Cell 2017 Oct 26. DOI: 10.1016/j.cell.2017.10.001.

A nonimmune function of T cells in promoting lung tumor progression

Amphiregulin (from the RCSB PDB)

Amphiregulin (Areg), a ligand for the epidermal growth factor receptor, was found to be produced by intratumoral regulatory and conventional CD4⁺ T cells. Areg was a positive factor in tumor growth, but a T cell–restricted deficiency of Areg did not impact antitumor immunity. Areg's effects were likely indirect, working through tumor-supportive stromal tissue.

Green JA, …, Rudensky AY. J Exp Med 2017 Oct 16. DOI: 10.1084/jem.20170356.

Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy

Neutrophils (from Manuel et al. Cancer Immunol Res 2014)

c-MET primarily promotes oncogenesis when expressed on tumor cells, but inhibiting c-MET can also enhance antitumor immunity. This antitumor effect is due to inhibition of c-MET signaling in neutrophils, which prevents their recruitment to, and suppressive influence on, the tumor microenvironment, increasing the efficacy of adoptive T-cell and checkpoint immunotherapies.

Glodde N, …, Hölzel M. Immunity 2017 Oct 17;47:789–802.e9.

An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism

Long noncoding RNA (from Rfam Database via Wikimedia)

Viral infection can induce a long noncoding RNA (lncRNA-AC0D1) that, independent of type 1 interferons or the IRF3 pathway, enhances viral replication; eliminating it reduces viral titers. lncRNA-AC0D1 directly binds to GOT2, a key metabolic enzyme that mediates lncRNA-AC0D1 effects. Mutational and functional analyses revealed that lncRNA binding enhanced GOT2 catalytic activity. Intervening with this metabolic pathway in metabolically dysregulated settings such as tumor microenvironments may prove useful.

Wang P, …, Cao X. Science Oct 26. DOI: 10.1126/science.aao0409.

Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial

Unanticipated beneficial outcomes (from N. Potanin via Flickr)

A clinical trial with 10,000 atherosclerosis patients (CANTOS) measured the effects of canakinumab, an antibody to IL1β, on cardiac events and also tracked the frequency of subsequent tumors. Those developing lung cancer had higher baseline IL6 and C-reactive protein. Lung, unlike other cancers, arose significantly less frequently if patients received canakinumab, supporting this pathway's importance in lung cancer and highlighting it for potential targeting.

Ridker PM, …, Glynn RJ. Lancet 2017 Oct 21;390:1833–42.