Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well ...understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses. Antibiotic-mediated depletion or gnotobiotic exclusion of fungi enhances responsiveness to radiation, whereas antibiotic-mediated depletion of bacteria reduces responsiveness and is associated with overgrowth of commensal fungi. Further, elevated intratumoral expression of Dectin-1, a primary innate sensor of fungi, is negatively associated with survival in patients with breast cancer and is required for the effects of commensal fungi in mouse models of radiation therapy.
Display omitted
•Commensal bacteria support antitumor T cell responses following radiation therapy•Depletion of intestinal bacteria leads to expansion of commensal fungal populations•Commensal fungi promote pro-tumor macrophage actions by impeding antitumor T cells•Tumor-associated macrophages sense fungi through a Dectin-1-mediated mechanism
Depletion of commensal bacteria leads to expansion of commensal fungi and reduced antitumor immunity following irradiation of tumors. Targeting commensal fungi enhanced the radiation-induced antitumor immune response by reducing macrophage-mediated immunosuppression. Thus, Shiao et al. demonstrate opposing effects of commensal bacteria and fungi on antitumor immunity following radiation.
Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not ...only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn’s disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn’s disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD.
Display omitted
•M. restricta is associated with the colonic mucosa in Crohn’s disease (CD) patients•M. restricta exacerbates colitis in wild-type and gnotobiotic mice•M. restricta is found in CD patients with a disease-linked polymorphism in CARD9•Malassezia-exacerbated colitis in mice requires signaling via CARD9
Limon et al. surveyed intestinal wall-associated fungi in patients with Crohn’s disease (CD) and healthy controls and found a common commensal skin yeast called Malassezia, preferentially in CD patients. Malassezia exacerbates colitis in mouse models through mechanisms requiring CARD9, a signaling protein involved in anti-fungal immunity.
Therapies targeting oncogene addiction have had a tremendous impact on tumor growth and patient outcome, but drug resistance continues to be problematic. One approach to deal with the challenge of ...resistance entails extending anticancer treatments beyond targeting cancer cells by additionally altering the tumor microenvironment. Understanding how the tumor microenvironment contributes to the evolution of diverse resistance pathways could aid in the design of sequential treatments that can elicit and take advantage of a predictable resistance trajectory. Tumor-associated macrophages often support neoplastic growth and are frequently the most abundant immune cell found in tumors. Here, we used clinically relevant in vivo Braf-mutant melanoma models with fluorescent markers to track the stage-specific changes in macrophages under targeted therapy with Braf/Mek inhibitors and assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ monocyte-derived macrophage infiltration rose, suggesting that macrophage influx at this point could facilitate the onset of stable drug resistance that melanoma cells show after several weeks of treatment. Comparison of melanomas that develop in a Ccr2-proficient or -deficient microenvironment demonstrated that lack of melanoma infiltrating Ccr2+ macrophages delayed onset of resistance and shifted melanoma cell evolution towards unstable resistance. Unstable resistance was characterized by sensitivity to targeted therapy when factors from the microenvironment were lost. Importantly, this phenotype was reversed by coculturing melanoma cells with Ccr2+ macrophages. Overall, this study demonstrates that the development of resistance may be directed by altering the tumor microenvironment to improve treatment timing and the probability of relapse.
Ccr2+ melanoma macrophages that are active in tumors during the drug-tolerant persister state following targeted therapy-induced regression are key contributors directing melanoma cell reprogramming toward specific therapeutic resistance trajectories.
Chronic viral infections, such as HIV and hepatitis C virus, represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral ...infections, the underlying mechanisms remain unknown. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (lymphocytic choriomeningitis virus clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially became effector cells early in chronic infection compared with adult CD8+ T cells and expressed higher levels of genes associated with cell migration and effector cell differentiation. During the chronic phase of infection, the neonatal cells retained more immune functionality and expressed lower levels of surface markers and genes related to exhaustion. Because the neonatal cells protect from viral replication early in chronic infection, the altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influence key cell fate decisions during chronic infection.
Abstract
Lin28b serves as a master regulator of fetal lymphopoiesis and promotes the development of more innate-like lymphocytes in early life. However, it is still unclear how Lin28b alters the ...function of CD8+ T cells and protects the host against infection. In this report we examined how Lin28b transcriptionally and epigenetically programs neonatal CD8+ T cells for innate immune defense. We found that murine neonatal CD8+ T cells possess innate-like transcriptomes, are more responsive to innate cytokines in the absence of antigen and produce a broader spectrum of cytokines compared to their adult counterparts. This unique program of bystander activation in early life corresponded with enhanced innate-like protection against irrelevant strains of bacterial, helminth and virus infections. To understand how this diversity of immune function is mediated, we used flow cytometry and scRNAseq and discovered that the neonatal CD8+ T cell pool is composed of many subsets of cells expressing distinct cytokines. ATACseq analysis revealed that neonatal CD8+ T cells are programmed to display innate-like properties and produce a diverse array of cytokines, which may be due to their ability to undergo extensive chromatin remodeling upon cytokine stimulation. These unique properties may be driven by high Lin28b expression in fetal progenitor cells, as adult cells expressing Lin28b initiated a program of bystander activation and immune protection that was analogous to neonates. Collectively, our data suggests that Lin28b enables neonatal CD8+ T cells to undergo a more diverse program of bystander activation, allowing them to deploy a bet-hedging immune strategy and protect the host against a rapidly changing pathogenic environment.
SIRT5 is a member of the sirtuin family of NAD
-dependent protein lysine deacylases implicated in a variety of physiological processes. SIRT5 removes negatively charged malonyl, succinyl, and ...glutaryl groups from lysine residues and thereby regulates multiple enzymes involved in cellular metabolism and other biological processes. SIRT5 is overexpressed in human breast cancers and other malignancies, but little is known about the therapeutic potential of SIRT5 inhibition for treating cancer. Here we report that genetic SIRT5 disruption in breast cancer cell lines and mouse models caused increased succinylation of IDH2 and other metabolic enzymes, increased oxidative stress, and impaired transformation and tumorigenesis. We, therefore, developed potent, selective, and cell-permeable small-molecule SIRT5 inhibitors. SIRT5 inhibition suppressed the transformed properties of cultured breast cancer cells and significantly reduced mammary tumor growth in vivo, in both genetically engineered and xenotransplant mouse models. Considering that Sirt5 knockout mice are generally normal, with only mild phenotypes observed, these data establish SIRT5 as a promising target for treating breast cancer. The new SIRT5 inhibitors provide useful probes for future investigations of SIRT5 and an avenue for targeting SIRT5 as a therapeutic strategy.
PDF
