Mutations in epidermal growth factor receptor (EGFR) are oncogenic drivers in non-small cell lung cancer (NSCLC), and as a result, tyrosine kinase inhibitors such as erlotinib have been approved for NSCLC patients. Rash, which is a major adverse effect of EGFR inhibition, impacts quality of life as well as patient compliance. Interestingly, rash resulting from EGFR inhibition has been correlated with positive efficacy, and therefore, rash prevention has been controversial. Melosky and colleagues recently reported the results of a randomized, prospective investigator-initiated phase II trial conducted in Canada to assess rash treatment and efficacy in advanced NSCLC patients. While treatment did not decrease the occurrence of rash following EGFR inhibition, prophylactic or reactive minocycline treatment decreased the severity of rash without compromising efficacy. This simple and inexpensive treatment method serves as an acceptable means for treating rash in these patients, likely improving the quality of life as well as the adherence to EGFR inhibitor treatment regimes. (J Clin Oncol 33:JCO.2015.62.3918, 2015) Selected by H. Williams
The tolerance of self
Self-tolerance is generated via promiscuous expression of peripheral tissue-restricted antigens (TRAs) by medullary thymic epithelial cells (mTECs) in order to remove T cells that respond to self-antigens. Takaba and colleagues identified the key transcription factor Fezf2 in the expression of TRAs and the establishment of immune self-tolerance in mTECs in the thymus. Fezf2 regulates TRA expression independently from Aire, a transcriptional regulator that is essential for promiscuous TRA expression and negative selection. Furthermore, loss of Fezf2 in mTECs leads to autoimmune disorders in mice. Receptor activator of nuclear factor-κB/CD40 and lymphotoxin beta receptor regulate the induction of distinct TRA genes via signaling through Aire and Fezf2, respectively. Fezf2-dependent TRA genes are known to include genes related to both autoimmune and neoplastic diseases, emphasizing the clinical relevance of these findings. Thus, Fezf2 function is required to establish central tolerance and to curb undesirable immune reactions in an Aire-independent manner. (Cell 163:975–987, 2015) Selected by M. Amagai
Development of Th17 cells in the intestinal lamina propria is induced in response to colonization by a subgroup of the gut microbiota. Atarashi and colleagues demonstrated that segmented filamentous bacteria (SFB), Citrobacter rodentium, and Escherichia coli O157 promote this induction via adhesion to intestinal epithelial cells. In addition, these investigators isolated 20 bacterial strains from the human intestine that induced Th17 cells in mouse or rat intestines. Thus, the intestinal immune system seemingly generates Th17 cell responses as a result of recognition of a physical interaction with the microbes as opposed to recognition of a released microbial component. In these studies, Th17 and IgA+ cells control epithelial cell-adhering microbes, whereas other gut microbes elicit other immune responses, suggesting that the host immune system may have evolved to discriminate the biogeographical distributions of intestinal microbes. Moving forward, these findings offer clinical implications for inflammatory bowel disease, vaccine design, and probiotics. (Cell 163:367–380, 2015) Selected by M. Amagai
Timing is everything
Research examining the role of commensal microbes in human health has focused on the intestinal tract, but as the skin barrier influences the immune system, commensal skin colonization is also an important area for investigation. Thus, Scharschmidt and colleagues generated a murine system to examine adaptive antigen-specific immune tolerance to an engineered strain of the commensal bacteria Staphylococcus epidermis in the skin. These studies revealed that commensal antigens were recognized locally and systemically across an intact skin barrier, inducing expansion of commensal-specific CD4+ T cells. Importantly, colonization of adult animals did not induce immune tolerance; however, neonatal colonization induced antigen-specific tolerance with an abrupt enrichment of commensal-specific activated Treg cells in the skin. Taken together, these findings indicate that composition of the skin microbiome in this defined developmental window of neonatal life exerts formative effects on commensal-specific adaptive immune responses, supporting the possibility that perturbations in such colonization may have clinical implications. (Immunity 43:1011–1021, 2015) Selected by M. Amagai
Cancer arises through an accumulation of genetic alterations. Although large-scale sequencing projects have identified mutations in melanoma, these studies have typically examined advanced tumors, preventing the inference of the order of mutation acquisition. As melanomas often arise from distinct precursors, examination of these stages may shed light on the genetic evolution of melanomas. Shain and colleagues sequenced 293 cancer-relevant genes from 37 primary melanomas and the adjacent precursor lesions and identified a stereotypical pattern of melanoma evolution. The progression began with MAPK-activating mutations followed by telomerase-activating mutations and then mutations that disrupt the G1-S checkpoint. The benign lesions harbored only the BRAFV600E mutation, while other lesions harbored multiple oncogenic alterations with distinct histopathological features, confirming an intermediate category of melanocytic neoplasia. Identification of the genetic alterations that lead to primary melanomas and documentation of their emergence during the stages of melanoma may lead to discovery of biomarkers that would ultimately improve diagnosis and prognostication. (N Engl J Med 373:1926–1936, 2015) Selected by B. Gilchrest
© 2015 The Author. Published by Elsevier Inc.