Alison Farrell

Defeating T-cell fatigue in HIV

HIV causes a chronic infection that overwhelms the immune system and leads to T-cell exhaustion. Three groups now report that a signaling molecule that dampens immune responses may tucker out the T cells (1198–1202).

A close look at cancer

We asked experts in cancer research to identify the most influential publications of the last two years. Here we summarize their responses and highlight some of the hot topics in this field.

Immunology: Spreading inflammation

A recent study utilizing human and mouse breast, colon and lung tumor models has shown that in response to withdrawal of therapy with sunitinib or sorafenib—which are receptor tyrosine kinase inhibitors considered to be antiangiogenic—tumors shift to lipogenesis, rapid regrowth and metastasis. Inhibiting lipogenesis with orlistat could reduce tumor regrowth, suggesting a new avenue to sensitize tumors. (Cell Metab. doi:10.1016/j. cmet.2014.05.022, 2014). Agnes Noel and her colleagues performed global transcriptomic and proteomic analyses to examine the changes underlying the accelerated growth and metastasis observed after withdrawal of sunitinib or sorafenib therapy in mice bearing human MDA-MB-231 breast carcinoma xenografts. Similar changes in tumor growth have been observed in response to anti– VEGFR-2 and anti-VEGF therapies. Analysis of tumors during sunitinib or sorafenib treatment showed increased glycolysis. However, upon treatment withdrawal, lipid metabolism and regulation were altered, resulting in a boost in fatty acid, pyruvate and amino acid metabolism. Fatty acid synthase (FASN) expression increased, suggesting a shift toward de novo lipogenesis. The authors then treated MDA-MB-231 or HT-29 xenografts and syngeneic mouse models with orlistat, a fatty acid synthase inhibitor, after sunitinib therapy withdrawal, and they noted reduced tumor growth and inhibited metastasis formation without effects on wholebody metabolic profiles. Treatment with antiangiogenic therapies can lead to more aggressive tumors after therapy withdrawal. Future studies may opt to employ FASN inhibition after therapy cessation to avert such deleterious effects in patients. —KS

A vaccine for tuberculosis

In combination, tumor mutational burden and the immunological state of the tumor microenvironment predict clinical responses to programmed death–1 (PD-1) inhibition across tumor types. Immune checkpoint–blocking antibodies have yielded unprecedented antitumor responses in patients; however this treatment is not effective in all patients, and biomarkers that predict clinical efficacy are lacking. Razvan Cristescu et al. perform analyses of clinical samples from patients collectively diagnosed with 22 different tumor types who were enrolled in trials assessing the effect of the anti-PD-1 antibody pembrolizumab in patients with cancer. The combination of high tumor mutational burden and a gene expression program reflecting T cell activation predict the highest rates of response to PD-1 blockade. This study provides clinically relevant biomarkers for predicting response to cancer immunotherapy. JC

Dengue virus: An enhanced model for dengue virus

inducing this gene expression program and in maintaining these macrophages at this location, which helped ameliorate inflammation. Functionally, activation of GATA6 by retinoic acid in these macrophages regulated the production of IgA by peritoneal B-1 immune cells. Looking at other downstream effects of GATA6, Marcela Rosas and her colleagues found that mice lacking Gata6 had altered proliferation of tissue macrophages during homeostasis. In a mouse model of acute peritonitis, the absence of this factor inhibited recovery of macrophages and resulted in delayed resolution of inflammation. Although the authors did not pinpoint what induces GATA6 in peritoneal macrophages, ex vivo cultures confirmed that a local tissue signal was needed.—CP

Notable advances 2015.

This year saw a whirlwind of insights gleaned into topics ranging from heart cell proliferation to organoid modeling. Here are a few of the research papers detailing some of these intriguing discoveries.

Immunity: Selective need for a CTP synthase

Eosinophils in energy homeostasis Two recent studies in Cell have provided mechanistic insight into the interactions of adipose tissue and the immune system in the regulation of energy expenditure and glucose tolerance (Cell 157, 1279–1291, 2014, and Cell 157, 1292–1308, 2014). In previous studies, Bruce Spiegelman and his colleagues showed that Pgc-1a4 is a unique isoform form of Pgc-1a that is expressed in mouse muscle during exercise and that exercise in mice induces ‘beiging’ of the white fat. In their new study, they link these previous findings by identifying meteorin-like (Metrnl) as a protein induced by Pgc-1a4 in skeletal muscle in mice and humans and one that promotes beiging and improved glucose tolerance— its expression is also induced by cold exposure in mouse adipose. Mechanistically, Metrnl expression is associated with recruitment to adipose tissue of eosinophils. This resulted in the Metrnl-dependent expression of the cytokines interleukin-4 (IL-4) and IL-13 in the adipose and promotion of the alternate activation of macrophages, thus possibly further explaining the increased insulin sensitivity upon Metrnl expression. In a separate study, Ajay Chawla and his colleagues found that cold exposure of mice results in alternative activation of macrophages in white adipose tissue in response to eosinophil recruitment and their IL-4 secretion. They further found that these alternatively activated macrophages are a key source of catecholamines that result in beiging of the local white adipose tissue. At thermoneutrality, they could replicate the effects of cold exposure, including the increase in beige fat mass and the reversal of established diet-induced obesity and insulin resistance, by treating mice with IL-4. —HS

Our antigens, our selves

Alison Farrell is a Senior Editor at Nature Medicine. The second section of the book extends our understanding of the importance of HLAs beyond the setting of transplantation to other diseases, including autoimmunity and HIV infection, and delves into the concept of variability in HLA genes and its role in disease susceptibility. At the end of this section, the author presents the discovery of NK cells and their function in distinguishing self from nonself, where NK cells can detect the absence of self HLA on foreign cells rather than the presence of nonself antigens. Towards the end of the book, Davis goes on to cover more preliminary findings that associate MHC genes with neural development, sexual compatibility and pregnancy. Here the book covers more uncertain territory—areas that are as yet unresolved and mechanistically unclear. Although the research in these areas is provocative, the findings are either not described in depth or the depth of our understanding is not yet great. The author does a good job at humanizing the scientists he describes. He introduces the reader to Medawar and to his family life, describing his interactions with World War II burn victims as the impetus to his studies on skin grafts, which resulted in our understanding of graft rejection and the ability to induce graft tolerance in animals. The reader is led to appreciate the time, effort, devotion and personal cost expended by the researchers driven to ask and try to answer these key scientific questions, as well as the collaborations required to achieve great results; notably, the contributions of these collaborators were not always equitably recognized. Davis reflects on the camaraderie and the competition among scientists of strong opinions and competing views, as well as the not infrequent opposition of the scientific community to new concepts or hypotheses. The writing is not always linear—rather, Davis attempts to give a reasonably full picture of some of the central players involved in the major discoveries before moving on to detail the next prominent scientist or advance. This works in some instances, but a broader view of the contributions (less focused on a handful of selected individuals) and their reception at the time (to the extent that there is a record) would be of interest to the reader, in my view. Moreover, some contributions are mentioned only briefly—such as those of Peter Gorer, a contemporary of Medawar and Burnet who recognized the genetic component of transplant rejection—and the focus of the book is primarily on European and Australian researchers. Nevertheless, the reader does come away with a rich appreciation of some of the landmark findings in immunology. Where the writing may reflect an attempt to interest a lay audience is, I think, where it is the weakest—such as referring in a single sentence to a scientist’s purported interest in sadism and masochism or in detailing the untimely death of Harvard structural biologist Don Wiley, anecdotes that inform the reader very little with respect to understanding the role of HLAs in immunity. Yet there is much to enjoy in this book even for the lay reader who is interested in an accessible account of some of the major scientific players in immunology, their discoveries and the broad relevance of HLAs and immune recognition of self and nonself to human disease. For any scientist who is not an immunologist, trying to make sense of the complexity of the major histocompatibility complex (MHC) genes and their role in immunity is a daunting task. To try to do so for a lay audience is far harder. But Daniel M. Davis has attempted just that in his detailed account of the studies surrounding the discovery of the MHC and the scientific insights that have since been derived from it that extend far beyond the immune system. The book is divided into three sections that loosely follow the timeline of discoveries on MHC. The first section of the book provides a historical account and perspective of the early studies that revealed the ability of the body to distinguish self from nonself and that eventually led to an understanding of its molecular underpinnings. We are introduced to Peter Medawar, whose work on skin grafts beginning in the 1940s helped form the foundation of our future understanding of how the immune system recognizes self and nonself and the role of MHC genes in this process. Frank Macfarlane Burnet and Medawar worked independently to discover acquired immunological tolerance—a state in which the immune system is unresponsive to an antigen that would normally stimulate it—which won them both the Nobel Prize in Physiology or Medicine in 1960. Burnet would later go on to formulate the idea of clonal selection that gives rise to antibody specificity. The early revelations of these and many other now prominent scientists, some of whom are also Nobel Prize winners, as well as the initial resistance to some of their ideas, are chronicled so that the reader can envisage how they shaped both the scientific community’s views and research in immunology. From a scientist reader’s viewpoint, the book presents a window into a prolific period of novel insights, early hypotheses that have since been rejected and groundbreaking discoveries that have culminated in our understanding of T, B and natural killer (NK) cells and their roles in mediating immune recognition. The first part of the book ends with the literal and figurative crystallization of MHC, detailing the work that finalized the structure of one of the human leukocyte antigens (HLAs, which correspond to the MHC proteins in humans) that are responsible for much of human self versus nonself recognition. Our antigens, our selves

Microbiome: Microbial mediators

patterns of GISTs from patients and found a strong divergence between SDH-deficient GISTs and GISTs that still expressed functional SDH. The SDH-deficient GISTs had greater amounts of genomic hypermethylation compared with the other tumor types, which the authors attributed to defective maintenance of epigenetic marks. Notably, this nonrandom pattern of epigenomic changes in SDH-deficient GISTs correlated with lower genomic stability compared to SDH-proficient tumors, and it is also present in other tumor types characterized by SDH deficiency. These results provide a link between mitochondrial function and epigenomic homeostasis that may have further implications for cancer etiopathology. —VA

Inflammation: Stemming colitis

Tranexamic acid (TXA) and e-aminocaproic acid (EACA), two antifibrinolytic drugs used to minimize blood loss during surgery, can cause seizures. A recent study (J. Clin. Invest. 122, 4654–4666, 2012) identifies glycine-receptor inhibition as a possible mechanism for this side effect and suggests a possible way to prevent it. TXA and EACA bear some structural similarity to glycine, inhibition of which triggers epilepsy. Might both compounds promote seizures by interfering with glycine-mediated neurotransmission? Studying mouse neurons and brain slices, Irene Lecker et al. found that, indeed, both drugs competitively antagonize glycine receptors. Moreover, the concentration of TXA in the cerebrospinal fluid of patients undergoing surgery was similar to concentrations with inhibitory potency in vitro. As patients treated with TXA and EACA often experience seizures after coming out of anesthesia, the authors went on to show that the anesthetics isoflurane and propofol reduced the inhibitory effect of the antifibrinolytic drugs. This observation raises the possibility of using these general anesthetics to prevent TXAand EACA-induced epileptic activity.—JCL