Immunoprofiling at an Institutional Scale Reveals That High Numbers of Intratumoral CD8 and PD-1 Cells Predict Superior Patient Survival Across Major Cancer Types Independent of Major Risk Factors.

Purpose: Retrospective studies have found associations between the number of intratumoral immune cells and patient outcomes for specific cancers treated with targeted therapies. However, the clinical value of routinely quantifying intratumoral immune biomarkers using a digital pathology platform in the pan-cancer setting within an active clinical laboratory has not been established.

Methods: We developed ImmunoProfile, a daily clinical workflow that integrates automated multiplex immunofluorescence tissue staining, digital slide imaging, and machine learning-assisted scoring to quantify intratumoral CD8, PD-1, CD8PD-1, and FOXP3 immune cells and PD-L1 expression in formalin-fixed, paraffin-embedded tissue samples in a standardized and reproducible manner.

Tumor Immunophenotypic Correlates in Patients Aged 80 Years or Older With Non-Small Cell Lung Cancer and Outcomes to First-Line Pembrolizumab in PD-L1 High (≥50%) Patients.

Background: Non-small cell lung cancer (NSCLC) patients aged ≥80 years [y] are underrepresented in clinical trials. We evaluated whether age correlates with a distinct immunophenotype or impacts outcomes to first-line pembrolizumab in patients with advanced NSCLC, PD-L1 Tumor Proportion Score (TPS) of ≥50%, and aged ≥80y.

Methods: Three NSCLC cohorts were retrospectively analyzed to assess the impact of age (<80y versus ≥80y) on pembrolizumab efficacy and the tumor microenvironment (TME).

ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer.

Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer.

Impact of Aneuploidy and Chromosome 9p Loss on Tumor Immune Microenvironment and Immune Checkpoint Inhibitor Efficacy in NSCLC.

Introduction: Although gene-level copy number alterations have been studied as a potential biomarker of immunotherapy efficacy in NSCLC, the impact of aneuploidy burden and chromosomal arm-level events on immune checkpoint inhibitor (ICI) efficacy in NSCLC is uncertain.

Methods: Patients who received programmed cell death protein 1 or programmed death-ligand 1 (PD-L1) inhibitor at two academic centers were included. Across all 22 chromosomes analyzed, an arm was considered altered if at least 70% of its territory was either gained or deleted.

Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non-Small Cell Lung Cancer.

Purpose: ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC); however, limited characterization has been pursued.

Experimental Design: Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations.

An AP-3-dependent pathway directs phagosome fusion with Rab8 and Rab11 vesicles involved in TLR2 signaling.

Intracellular compartmentalization of ligands, receptors and signaling molecules has been recognized as an important regulator of inflammation. The toll-like receptor (TLR) 2 pathway utilizes the trafficking molecule adaptor protein 3 (AP-3) to activate interleukin (IL)-6 signaling from within phagosomal compartments. To better understand the vesicular pathways that may contribute to intracellular signaling and cooperate with AP-3, we performed a vesicular siRNA screen.

Association of High Tumor Mutation Burden in Non-Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels.

Importance: Although tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non-small cell lung cancer (NSCLC).

Objectives: To determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand-1 (PD-L1) levels in patients with NSCLC.

Design, Setting, And Participants: This multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death-1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets.

Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer.

Background: An elevated peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is a negative prognostic marker for patients with non-small cell lung cancer (NSCLC) receiving chemotherapy and immune checkpoint inhibitors. Whether dNLR is also associated with clinical outcomes to first-line pembrolizumab among patients with NSCLC and a programmed cell death ligand 1 (PD-L1) Tumor Proportion Score (TPS) of ≥50% is uncertain. How dNLR relates to the tumor immune microenvironment is also unclear.

SMARCA4 and Other SWItch/Sucrose NonFermentable Family Genomic Alterations in NSCLC: Clinicopathologic Characteristics and Outcomes to Immune Checkpoint Inhibition.

Introduction: The SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations (muts) within the complex are implicated in genomic instability, higher tumor mutational burden, and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear.

Methods: We collected clinicopathologic and genomic data from patients with NSCLC who underwent targeted next-generation sequencing at the Dana-Farber Cancer Institute.

Genetic Background Amplifies the Effect of Immunodeficiency in Antibiotic Efficacy Against Borrelia burgdorferi.

Unrecognized immunodeficiency has been proposed as a possible cause of failure of antibiotics to resolve symptoms of Lyme disease. Here, we examined the efficacy of doxycycline in different immunodeficient mice to identify defects that impair antibiotic treatment outcomes. We found that doxycycline had significantly lower efficacy in the absence of adaptive immunity, specifically B cells.

Design of a broadly reactive Lyme disease vaccine.

A growing global health concern, Lyme disease has become the most common tick-borne disease in the United States and Europe. Caused by the bacterial spirochete sensu lato (sl), this disease can be debilitating if not treated promptly. Because diagnosis is challenging, prevention remains a priority; however, a previously licensed vaccine is no longer available to the public.

Genome-wide screen identifies novel genes required for Borrelia burgdorferi survival in its Ixodes tick vector.

Borrelia burgdorferi, the causative agent of Lyme disease in humans, is maintained in a complex biphasic life cycle, which alternates between tick and vertebrate hosts. To successfully survive and complete its enzootic cycle, B. burgdorferi adapts to diverse hosts by regulating genes required for survival in specific environments.

Identifying Vancomycin as an Effective Antibiotic for Killing Borrelia burgdorferi.

is the causative agent of Lyme borreliosis. Antibiotic therapy of early acute infection is effective for most patients, but 10 to 20% go on to develop posttreatment Lyme disease syndrome (PTLDS). The nature of PTLDS remains unknown, but currently approved antibiotics for the treatment of Lyme disease do not appear to impact these symptoms after they have developed.

Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells.

Borrelia burgdorferi is the causative agent of Lyme disease, which affects an estimated 300,000 people annually in the United States. When treated early, the disease usually resolves, but when left untreated, it can result in symptoms such as arthritis and encephalopathy. Treatment of the late-stage disease may require multiple courses of antibiotic therapy.

Correlates of problematic unrecorded alcohol consumption in Sikkim, Northeast India - Results from a cross-sectional pilot survey.

The magnitude and consequences of unrecorded alcohol consumption, defined as home brewed or clandestinely produced illicit liquor or surrogate alcoholic beverage has been little investigated in India. A significant portion of all alcohol consumed globally is unrecorded, therefore these consumers constitute a significant population. Sikkim, a province in Northeast India, lies in the foothills of the Himalayas.