BackgroundOsteoclasts are the body’s sole bone resorbing cells. Cytokines produced by pro-inflammatory effector T-cells (TEFF) increase bone resorption by osteoclasts. Prolonged exposure to the TEFF produced cytokines leads to bone erosion diseases such as osteoporosis and rheumatoid arthritis. The crosstalk between T-cells and osteoclasts has been termed osteoimmunology. We have previously shown that under non-inflammatory conditions, murine osteoclasts can recruit naïve CD8 T-cells and activate these T-cells to induce CD25 and FoxP3 (TcREG). The activation of CD8 T-cells by osteoclasts also induced the cytokines IL-2, IL-6, IL-10 and IFN-γ. Individually, these cytokines can activate or suppress osteoclast resorption.Principal FindingsTo determine the net effect of TcREG on osteoclast activity we used a number of in vitro assays. We found that TcREG can potently and directly suppress bone resorption by osteoclasts. TcREG could suppress osteoclast differentiation and resorption by mature osteoclasts, but did not affect their survival. Additionally, we showed that TcREG suppress cytoskeletal reorganization in mature osteoclasts. Whereas induction of TcREG by osteoclasts is antigen-dependent, suppression of osteoclasts by TcREG does not require antigen or re-stimulation. We demonstrated that antibody blockade of IL-6, IL-10 or IFN-γ relieved suppression. The suppression did not require direct contact between the TcREG and osteoclasts.SignificanceWe have determined that osteoclast-induced TcREG can suppress osteoclast activity, forming a negative feedback system. As the CD8 T-cells are activated in the absence of inflammatory signals, these observations suggest that this regulatory loop may play a role in regulating skeletal homeostasis. Our results provide the first documentation of suppression of osteoclast activity by CD8 regulatory T-cells and thus, extend the purview of osteoimmunology.

T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the α and β chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of αβ TCR domains with corresponding γδ TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy.DOI: http://dx.doi.org/10.7554/eLife.19095.001

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer risk screening and treatment strategies. Using genotypes from over 8,000 European individuals in The Cancer Genome Atlas (TCGA) and 137 heritable tumor immune phenotype components (IP components), we identified and investigated 482 TIME associations and 475 unique TIME-associated variants. Many TIME-associated variants influence gene activities in specific immune cell subsets, such as macrophages and dendritic cells, and interact to promote more extreme TIME phenotypes. TIME-associated variants were predictive of immunotherapy response in human cohorts treated with immune-checkpoint blockade (ICB) in 3 cancer types, causally implicating specific immune-related genes that modulate myeloid cells of the TIME. Moreover, we validated the function of these genes in driving tumor response to ICB in preclinical studies. Through an integrative approach, we link host genetics to TIME characteristics, informing novel biomarkers for cancer risk and target identification in immunotherapy.

and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response', Cancer Research.

46Insights into oncogenesis derived from cancer susceptibility loci could facilitate 47 better cancer management and treatment through precision oncology. However, 48 therapeutic applications have thus far been limited by our current lack of 49 understanding regarding both their interactions with somatic cancer driver mutations 50 and their influence on tumorigenesis. Here, by integrating germline datasets relating 51 to cancer susceptibility with tumour data capturing somatically-acquired genetic 52 variation, we provide evidence that single nucleotide polymorphism (SNPs) and 53 somatic mutations in the p53 tumor suppressor pathway can interact to influence 54 cancer development, progression and treatment response. We go on to provide human 55 genetic evidence of a tumor-promoting role for the pro-survival activities of p53, 56 which supports the development of more effective therapy combinations through their 57 inhibition in cancers retaining wild-type p53. 58 59Significance 60 We describe significant interactions between heritable and somatic genetic variants 61 in the p53 pathway that affect cancer susceptibility, progression and treatment 62 response. Our results offer evidence of how cancer susceptibility SNPs can interact 63 with cancer driver genes to affect cancer progression and identify novel therapeutic 64 targets. 65 affect p53's ability to bind to DNA in a sequence-specific manner and regulate 99 transcription of its target genes. Some of these same TP53 mutations when found 100 constitutionally result in Li-Fraumeni Syndrome: a syndrome comprising dramatic 101 increase in cancer risk in many tissues types. Although targeting driver mutations in 102 tumor suppressors has been challenging, the high abundance of p53 mutations in 103 cancer has motivated the development of small molecules that aim to reactivate 104 mutant p53 to increase sensitivities to DNA-damaging therapies or inhibit gain-of 105 function activities (15). 106Somatic driver mutations in other p53 pathway genes are also current drug 107 targets. In a sub-set of p53 wild-type cancers, p53 signaling can be attenuated through 108 somatic driver events that alter key p53 regulators. For example, the MDM2 109 oncogene is amplified in a variety of cancers. Its amplification results in decreased 110 p53-mediated tumor suppression, increased cancer susceptibility, and the reduction of 111 selection pressures for somatic p53 mutations (16). Moreover, cancer cells with 112 amplified MDM2 and wild-type p53 have an attenuated p53-mediated DNA damage 113 response (17). Thus, amplification of MDM2 is a promising target for treatment, in 114 combination with DNA-damaging therapies (15,18). 115Most studies have separately examined the consequences of somatic and 116 germline variation affecting p53 activity to understand their roles in disease risk, 117 progression or response to therapy. Here we hypothesize that cancer-associated 118 germline variants (single nucleotide polymorphisms, SNPs) interact with p53 somatic 119 driver mutations to modify c...

SUMMARYExtrachromosomal circular DNA (ecDNA) is an important driver of aggressive tumor growth, promoting high oncogene copy number, intratumoral heterogeneity, accelerated evolution of drug resistance, enhancer rewiring, and poor outcome. ecDNA has been reported in medulloblastoma (MB), the most common malignant pediatric brain tumor, but the ecDNA landscape and its association with specific MB subgroups, its impact on enhancer rewiring, and its potential clinical implications, are not known. We assembled a retrospective cohort of 468 MB patient samples with available whole genome sequencing (WGS) data covering the four major MB subgroups WNT, SHH, Group 3 and Group 4. Using computational methods for the detection and reconstruction of ecDNA1, we find ecDNA in 82 patients (18%) and observe that ecDNA+ MB patients are more than twice as likely to relapse and three times as likely to die of disease. In addition, we find that individual medulloblastoma tumors often harbor multiple ecDNAs, each containing different amplified oncogenes along with co-amplified non-coding regulatory enhancers. ecDNA was substantially more prevalent among 31 analyzed patient-derived xenograft (PDX) models and cell lines than in our patient cohort. By mapping the accessible chromatin and 3D conformation landscapes of MB tumors that harbor ecDNA, we observe frequent candidate “enhancer rewiring” events that spatially link oncogenes with co-amplified enhancers. Our study reveals the frequency and diversity of ecDNA in a subset of highly aggressive tumors and suggests enhancer rewiring as a frequent oncogenic mechanism of ecDNAs in MB. Further, these results demonstrate that ecDNA is a frequent and potent driver of poor outcome in MB patients.

Importance: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man's risk of dying from prostate cancer and thus inform screening decisions, especially in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Objective: Determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Design: Million Veteran Program (MVP) cohort study, 2011-2021. Setting: Nation-wide study of United States military veterans. Participants: Population-based volunteer sample of male participants. Exposure(s): Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. Main Outcome(s) and Measure(s): Study designed after MVP data collected. Primary outcome: age at death from prostate cancer. Key secondary outcome: age at diagnosis of prostate cancer metastases. Hypothesis: A germline genetic score (PHS290) is associated with risk of fatal (or metastatic) prostate cancer. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group (p<1e-16). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio for death from prostate cancer was 4.41 [95% CI: 3.9-5.02]. Corresponding hazard ratios for European, African, Hispanic, and Asian subsets were 4.26 [3.66-4.9], 2.4 [1.77-3.23], 4.72 [2.68-8.87], and 10.46 [2.01-101.0]. When accounting for family history and ancestry group, PHS290 remained a strong independent predictor of fatal prostate cancer. PHS290 was also associated with metastasis. PHS290 was higher, on average, among men with African ancestry. Conclusions and Relevance: PHS290 stratified US veterans of diverse ancestry for lifetime risk of metastatic or fatal prostate cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.