Purpose: DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features. Experimental Design: We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically. Results: BRCA2, ATM, and CDK12 were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele–specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous BRCA2 deletions. Tumor suppressors TP53, RB1, and PTEN were controlled via disruptive chromosomal rearrangements in BRCA2-defective samples, but via oncogene amplification in context of CDK12 defects. TP53 mutations were rare in cases with ATM defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of BRCA2 and CDK12, but not ATM, was associated with poor clinical outcomes. Conclusions: BRCA2, ATM, and CDK12 defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.

SUMMARYThe host response to infection requires an immune response to be strong enough to control the pathogen but also restrained, to minimize immune-mediated pathology. The conflicting pressures of immune activation and immune suppression are particularly apparent in parasite infections, where co-evolution of host and pathogen has selected many different compromises between protection and pathology. Cytokine signals are critical determinants of both protective immunity and immunopathology, and, in this review, we focus on the regulatory cytokine IL-10 and its role in protozoan and helminth infections. We discuss the sources and targets of IL-10 during parasite infection, the signals that initiate and reinforce its action, and its impact on the invading parasite, on the host tissue, and on coincident immune responses.

Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) are professional antigen presenting cells, essential for the initiation of adaptive immune responses. Heterogeneous DC populations exist, and different subsets have been associated with the development of discrete T-helper (Th) cell responses. In the spleen, CD8α + DCs were reported to secrete high levels of IL-12p70 and preferentially induce Th1 responses, 88Stephen A. Redpath et al. Eur. J. Immunol. 2018. 48: 87-98 function under homeostatic conditions [3][4][5][6][7], but their contribution during infection is less well understood. Helminth parasites are common pathogens of the human intestinal tract, infecting some 2 billion people worldwide [8]. Helminths typically induce strong Th2 cell responses, characterized by the cytokines IL-4, , and DCs are essential to this process [10][11][12] (Fig. 1C).This reduction was accompanied by an increase in the proportion and number of these DCs in the MLN (Fig. 1D). These data support a hypothesis that CD11b + CD103 + DCs leave the infection site upon helminth infection, and accumulate in the local lymph node. The proportion and number of CD11b + CD103 − DCs in the MLN also increased following H. polygyrus infection (Fig. 1F), although the number of these DCs did not decrease significantly in the SI-LP (Fig. 1E). MHCII than in the SI-LP, but there were no differences in expression of MHCII, CD40 or OX40L between the three populations, neither in naïve nor infected animals (Supporting Information Fig. 3 and data not shown). Interestingly, CD11b + CD103 − and CD11b + CD103 + DCs in the MLN showed higher expression of PDL2 following H. polygyrus infection compared to DCs in naïve mice ( Fig. 2A and B). PDL2 expression on CD103 + CD11b − DCs was unaffected by infection, although this subset showed high basal expression ( Fig. 2A and B). Thus, in the MLN, only CD11b + DCs upregulate the co-stimulatory molecule PDL2 in response to H. polygyrus infection.To further examine the nature of DC subset activation in response to helminth infection, we assessed the cytokine expression of each population. IL-6 and IL-10 have previously been associated with Th2 development in response to helminth antigens [31,32]. We analyzed gene expression for the cytokines IL-6, IL-10 and the canonical Th1 polarizing signal, in Fig. 2A and B), both subsets are IRF4-dependent, and both share developmental origins [3,6]. Our sort gates are illustrated in Supporting Information Fig. 4. During H. polygyrus infection, CD11b + DCs expressed more il6 than CD11b − DCs (Fig. 2C). CD11b + DCs also expressed 2 fold more il10 than did CD11b − DCs (Fig. 2C). In contrast, il12p40and il12p35 gene expression was 3 fold higher in CD11b − than in CD11b + DCs (Fig. 2C) ( Fig. 5C). Control wells containing T cells and DCs without peptide antigen produced very little cytokine, irrespective of DC subset (Supporting Information Fig. 9 to become Th2-inducing. To tes...

PURPOSE Pulmonary involvement is rare in metastatic hormone-sensitive prostate cancer (mHSPC) that recurs after treatment for localized disease. Guidelines recommend intensive systemic therapy, similar to patients with liver metastases, but some lung-recurrent mHSPC may have good outcomes. Genomic features of lung metastases may clarify disease aggression, but are poorly understood since lung biopsy is rarely performed. We present a comparative assessment of genomic drivers and heterogeneity in metachronous prostate tumors and lung metastases. METHODS We leveraged a prospective functional imaging study of 208 biochemically recurrent prostate cancers to identify 10 patients with lung-recurrent mHSPC. Histologic diagnosis was attained via thoracic surgery or fine-needle lung biopsy. We retrieved clinical data and performed multiregion sampling of primary tumors and metastases. Targeted and/or whole-exome sequencing was applied to 46 primary and 32 metastatic foci. RESULTS Unusually for mHSPC, all patients remained alive despite a median follow-up of 11.5 years. Several patients experienced long-term freedom from systemic treatment. The genomic landscape of lung-recurrent mHSPC was typical of curable prostate cancer with frequent PTEN, SPOP, and chromosome 8p alterations, and there were no deleterious TP53 and DNA damage repair gene mutations that characterize aggressive prostate cancer. Despite a long median time to recurrence (76.8 months), copy number alterations and clonal mutations were highly conserved between metastatic and primary foci, consistent with intrapatient homogeneity and limited genomic evolution. CONCLUSION In this retrospective hypothesis-generating study, we observed indolent genomic etiology in selected lung-recurrent mHSPC, cautioning against grouping these patients together with liver or bone-predominant mHSPC. Although our data do not generalize to all patients with lung metastases, the results encourage prospective efforts to stratify lung-recurrent mHSPC by genomic features.