Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity.

Natural Killer cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect Natural Killer cell gene expression is poorly understood. Here we perform expression quantitative trait locus mapping of negatively selected Natural Killer cells from a population of healthy Europeans (n = 245). We find a significant subset of genes demonstrate expression quantitative trait loci specific to Natural Killer cells and these are highly informative of human disease, in particular autoimmunity. A Natural Killer cell transcriptome-wide association study across five common autoimmune diseases identifies further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor region, GNLY, MC1R and UVSSA. Our findings provide new insights into the unique biology of Natural Killer cells, demonstrating markedly different expression quantitative trait loci from other immune cells, with implications for disease mechanisms.

Immune checkpoint blockade sensitivity and progression-free survival associates with baseline CD8+ T cell clone size and cytotoxicity.

The antitumor action of immune checkpoint blockade (ICB) is primarily mediated by CD8+ T cells. How sensitivity to ICB varies across CD8+ T cell subsets and clonotypes and the relationship of these with clinical outcome is unclear. To explore this, we used single-cell V(D)J and RNA-sequencing to track gene expression changes elicited by ICB across individual peripheral CD8+ T cell clones, identify baseline markers of CD8+ T cell clonal sensitivity, and chart how CD8+ T cell transcriptional changes vary according to phenotypic subset and clonal size. We identified seven subsets of CD8+ T cells with divergent reactivity to ICB and found that the cytotoxic effector subset showed the greatest number of differentially expressed genes while remaining stable in clonal size after ICB. At the level of CD8+ T cell clonotypes, we found a relationship between transcriptional changes and clone size, with large clones showing a greater number of differentially regulated genes enriched for pathways including T cell receptor (TCR) signaling. Cytotoxic CD8+ effector clones were more likely to persist following ICB and were more likely to correspond with public tumor-infiltrating lymphocyte clonotypes. Last, we demonstrated that individuals whose CD8+ T cell pretreatment showed low cytotoxicity and had fewer expanded clones typically had worse outcomes after ICB treatment. This work further advances understanding of the molecular determinants of ICB response, assisting in the search for peripheral prognostic biomarkers and highlighting the importance of the baseline CD8+ immune landscape in determining ICB response in metastatic melanoma.

Development of an adenovirus vector vaccine platform for targeting dendritic cells.

Adenoviral (Ad) vector vaccines represent one of the most promising modern vaccine platforms, and Ad vector vaccines are currently being investigated in human clinical trials for infectious disease and cancer. Our studies have shown that specific targeting of adenovirus to dendritic cells dramatically enhanced vaccine efficacy. However, this was achieved using a molecular adapter, thereby necessitating a two component vector approach. To address the mandates of clinical translation of our strategy, we here sought to accomplish the goal of DC targeting with a single-component adenovirus vector approach. To redirect the specificity of Ad vector vaccines, we replaced the Ad fiber knob with fiber-fibritin chimeras fused to DC1.8, a single-domain antibody (sdAb) specific for murine immature DC. We engineered a fiber-fibritin-sdAb chimeric molecule using the coding sequence for DC1.8, and then replaced the native Ad5 fiber knob sequence by homologous recombination. The resulting Ad5 virus, Ad5FF1.8, expresses the chimeric fiber-fibritin sdAb chimera. Infection with Ad5FF1.8 dramatically enhances transgene expression in DC2.4 dendritic cells compared with infection with native Ad5. Ad5FF1.8 infection of bone marrow-derived DC demonstrates that Ad5FF1.8 selectively infects immature DC consistent with the known specificity of DC1.8. Thus, sdAb can be used to selectively redirect the tropism of Ad5 vector vaccines, providing the opportunity to engineer Ad vector vaccines that are specifically targeted to DC, or specific DC subsets.

Recurrent Solid Pseudopapillary Neoplasm of Pancreas: Case Report and Review of Literature.

Background: Solid pseudopapillary neoplasm of pancreas is a rare tumor with a low potential for metastasis and recurrence. Long-term outcomes after surgical resection are excellent and recurrences after an R0 resection are extremely rare. Case Presentation: We present an unusual case of a 42-year-old man who had a recurrence of his solid pseudopapillary tumor 4 years after undergoing a distal pancreatectomy and splenectomy and then again a year after his reresection. Conclusions: The lack of histological features deemed to be suggestive of a malignant variant and the aggressive clinical course seen in this case is remarkable. It underscores the fact that despite the low incidence, recurrences of solid pseudopapillary neoplasms of the pancreas do occur and it can be very difficult to predict malignant potential based on radiological or histopathological features.

Personalized cancer vaccines: Targeting the cancer mutanome.

The development of next generation sequencing technologies has revolutionized our understanding of how specific genetic events contribute to cancer initiation and progression. Dramatic improvements in instrument design and efficiency, combined with significant cost reductions has permitted a systematic analysis of the mutational landscape in a variety of cancer types. At the same time, a detailed map of the cancer mutanome in individual cancers offers a unique opportunity to develop personalized cancer vaccine strategies targeting neoantigens. Recent studies in both preclinical models and human cancer patients demonstrate that neoantigens (1) are important targets following checkpoint inhibition therapy, (2) have been identified as the target of adoptive T cell therapies, and (3) can be successfully targeted with personalized vaccines. Taken together, these observations provide strong rationale for the clinical translation of personalized cancer vaccines.

Axillary Ultrasound Accurately Excludes Clinically Significant Lymph Node Disease in Patients With Early Stage Breast Cancer.

OBJECTIVE: Assess the performance characteristics of axillary ultrasound (AUS) for accurate exclusion of clinically significant axillary lymph node (ALN) disease. BACKGROUND: Sentinel lymph node biopsy (SLNB) is currently the standard of care for staging the axilla in patients with clinical T1-T2, N0 breast cancer. AUS is a noninvasive alternative to SLNB for staging the axilla. METHODS: Patients were identified using a prospectively maintained database. Sensitivity, specificity, and negative predictive value (NPV) were calculated by comparing AUS findings to pathology results. Multivariate analyses were performed to identify patient and/or tumor characteristics associated with false negative (FN) AUS. A blinded review of FN and matched true negative cases was performed by 2 independent medical oncologists to compare treatment recommendations and actual treatment received. Recurrence-free survival was described using Kaplan-Meier product limit methods. RESULTS: A total of 647 patients with clinical T1-T2, N0 breast cancer underwent AUS between January 2008 and March 2013. AUS had a sensitivity of 70%, NPV of 84%, and PPV of 56% for the detection of ALN disease. For detection of clinically significant disease (>2.0 mm), AUS had a sensitivity of 76% and NPV of 89%. FN AUS did not significantly impact adjuvant medical decision making. Patients with FN AUS had recurrence-free survival equivalent to patients with pathologic N0 disease. CONCLUSIONS: AUS accurately excludes clinically significant ALN disease in patients with clinical T1-T2, N0 breast cancer. AUS may be an alternative to SLNB in these patients, where axillary surgery is no longer considered therapeutic, and predictors of tumor biology are increasingly used to make adjuvant therapy decisions.

Immune checkpoints and immunotherapy for colorectal cancer.

Colorectal cancer (CRC) remains one of the major causes of death worldwide, despite steady improvement in early detection and overall survival over the past decade. Current treatment paradigms, with chemotherapy and biologics, appear to have reached their maximum benefit. Immunotherapy, especially with checkpoint inhibitors, has shown considerable clinical benefit in various cancers, including mismatch-repair-deficient CRC. This has led to the planning and initiation of several clinical trials evaluating novel immunotherapy agents-as single agents, combinations and in conjunction with chemotherapy-in patients with CRC. This article reviews biological and preclinical data for checkpoint inhibitors and discusses various immunotherapy trials in CRC, as well as current efforts in CRC immunotherapy.