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.

PD-L1, Tumor Mutational Burden, and Outcomes in NSCLC With Brain Metastases: A Brief Report.

Introduction: Patients with NSCLC and brain metastases have a poor prognosis. Combining brain-directed radiation therapy (RT) with immune checkpoint inhibitors (ICIs) may be synergistic. Nevertheless, predictors of response and toxicity are lacking.

Deep Learning Model for Predicting Immunotherapy Response in Advanced Non-Small Cell Lung Cancer.

Importance: Only a small fraction of patients with advanced non-small cell lung cancer (NSCLC) respond to immune checkpoint inhibitor (ICI) treatment. For optimal personalized NSCLC care, it is imperative to identify patients who are most likely to benefit from immunotherapy.

Objective: To develop a supervised deep learning-based ICI response prediction method; evaluate its performance alongside other known predictive biomarkers; and assess its association with clinical outcomes in patients with advanced NSCLC.

Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC.

Introduction: Patients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation.

Methods: We conducted a retrospective study using a multicenter study of 17 institutions globally.

Impact of Angiotensin Converting Enzyme Inhibitors on Pathologic Complete Response With Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer.

Introduction: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC).

Patients And Methods: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions.

Association of Baseline Tumor-Specific Neoantigens and CD8 T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors.

Purpose: Recent evidence has shown that higher tumor mutational burden strongly correlates with an increased risk of immune-related adverse events (irAEs). By using an integrated multiomics approach, we further studied the association between relevant tumor immune microenvironment (TIME) features and irAEs.

Methods: Leveraging the US Food and Drug Administration Adverse Event Reporting System, we extracted cases of suspected irAEs to calculate the reporting odds ratios (RORs) of irAEs for cancers treated with immune checkpoint inhibitors (ICIs).

Influence of Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint Inhibitors in -Mutant Non-Small-Cell Lung Cancer.

Purpose: Non-small-cell lung cancer (NSCLC) with has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring comutations could have favorable outcomes to ICIs.

Patients And Methods: NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes).

Consolidation Osimertinib Versus Durvalumab Versus Observation After Concurrent Chemoradiation in Unresectable EGFR-Mutant NSCLC: A Multicenter Retrospective Cohort Study.

Introduction: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown.

Methods: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022.

Benchmarking mismatch repair testing for patients with cancer receiving immunotherapy.

Immunohistochemistry (IHC) is currently the first-line test for mismatch repair deficiency (MMR-D). Bou Farhat et al. show that mismatch repair (MMR) mutation signature by next-generation sequencing is a highly sensitive assay capable of detecting MMR-D cases that are missed in 1% and 5% of patients with MMR-D colorectal cancer (CRC) and endometrial cancer (EC), respectively.

Treatment-related adverse events, including fatal toxicities, in patients with solid tumours receiving neoadjuvant and adjuvant immune checkpoint blockade: a systematic review and meta-analysis of randomised controlled trials.

Background: Incorporating immune checkpoint blockade into perioperative cancer therapy has improved clinical outcomes. However, the safety of immune checkpoint blockade needs better evaluation, given the chances of more prolonged disease-free survival. We aimed to assess how adding immune checkpoint blockade to perioperative therapy affects treatment-related adverse events.

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.

Epigenomic charting and functional annotation of risk loci in renal cell carcinoma.

While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC.

Germline variants associated with toxicity to immune checkpoint blockade.

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types.

Association of Machine Learning-Based Assessment of Tumor-Infiltrating Lymphocytes on Standard Histologic Images With Outcomes of Immunotherapy in Patients With NSCLC.

Importance: Currently, predictive biomarkers for response to immune checkpoint inhibitor (ICI) therapy in lung cancer are limited. Identifying such biomarkers would be useful to refine patient selection and guide precision therapy.

Objective: To develop a machine-learning (ML)-based tumor-infiltrating lymphocytes (TILs) scoring approach, and to evaluate TIL association with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC).

Angiotensin II receptor type 1 blockade regulates Klotho expression to induce TSC2-deficient cell death.

Lymphangioleiomyomatosis (LAM) is a multisystem disease occurring in women of child-bearing age manifested by uncontrolled proliferation of smooth muscle-like "LAM" cells in the lungs. LAM cells bear loss-of-function mutations in tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2, causing hyperactivation of the proliferation promoting mammalian/mechanistic target of Rapamycin complex 1 pathway. Additionally, LAM-specific active renin-angiotensin system (RAS) has been identified in LAM nodules, suggesting this system potentially contributes to neoplastic properties of LAM cells; however, the role of this renin-angiotensin signaling is unclear.

Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors.

The immune checkpoint inhibitor (ICI) pembrolizumab is US FDA approved for treatment of solid tumors with high tumor mutational burden (TMB-high; ≥10 variants/Mb). However, the extent to which TMB-high generalizes as an accurate biomarker in diverse patient populations is largely unknown. Using two clinical cohorts, we investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing in solid tumors.