Publications by authors named "Timothy A Chan"

Article Synopsis
  • Superficial malignant peripheral nerve sheath tumors (SF-MPNSTs) are rare cancers that share some features with spindle cell melanomas and desmoplastic melanomas, but their biological characteristics remain poorly understood.* -
  • A study comparing SF-MPNST to other tumor types through whole-exome and RNA sequencing found that SF-MPNST had an intermediate tumor mutational burden and distinct gene expression patterns, indicating differences among these cancer types.* -
  • Immunohistochemical analysis revealed notable differences in markers like H3K27me3 and PRAME between SF-MPNST and other cancers, suggesting potential for new diagnostic markers and insights into tumor behavior.*
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  • The "three Es" model describes how the immune system keeps cancer cells in check until they gain traits that allow them to escape immune detection.
  • A new framework called the "three Cs" explains how cancer cells evade the immune system through camouflage, coercion, and cytoprotection.
  • Improving cancer treatments requires blocking these escape mechanisms to enhance the effectiveness of both immunotherapy and conventional therapies.
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Neoantigen immunoediting drives immune checkpoint blockade efficacy, yet the molecular features of neoantigens and how neoantigen immunogenicity shapes treatment response remain poorly understood. To address these questions, 80 patients with non-small cell lung cancer were enrolled in the biomarker cohort of CheckMate 153 (CA209-153), which collected radiographic guided biopsy samples before treatment and during treatment with nivolumab. Early loss of mutations and neoantigens during therapy are both associated with clinical benefit.

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The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early-onset CRC [EOCRC]) has substantially increased, and yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. We compared tumor-associated T-cell repertoires between EOCRC and average-onset CRC (AOCRC) to uncover potentially unique immune microenvironment-related features by age of onset. Our discovery cohort included 242 patients who underwent surgical resection at Cleveland Clinic from 2000 to 2020.

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Immunologic recognition of peptide antigens bound to class I major histocompatibility complex (MHC) molecules is essential to both novel immunotherapeutic development and human health at large. Current methods for predicting antigen peptide immunogenicity rely primarily on simple sequence representations, which allow for some understanding of immunogenic features but provide inadequate consideration of the full scale of molecular mechanisms tied to peptide recognition. We here characterize contributions that unsupervised and supervised artificial intelligence (AI) methods can make toward understanding and predicting MHC(HLA-A2)-peptide complex immunogenicity when applied to large ensembles of molecular dynamics simulations.

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Tumors develop by invoking a supportive environment characterized by aberrant angiogenesis and infiltration of tumor-associated macrophages (TAMs). In a transgenic model of breast cancer, we found that TAMs localized to the tumor parenchyma and were smaller than mammary tissue macrophages. TAMs had low activity of the metabolic regulator mammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negative regulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibited tumor growth in a manner independent of adaptive lymphocytes.

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Purpose: A single arm, phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple-negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, overall survival (OS), and identify pathologic and transcriptomic correlates of response to therapy.

Patients And Methods: Patients with ≤2 prior therapies for metastatic disease were treated with CNP regardless of tumor programmed cell death-ligand 1 status. Core tissue biopsies were obtained prior to treatment initiation.

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The progression of cancer involves a critical step in which malignant cells escape from control by the immune system. Antineoplastic agents are particularly efficient when they succeed in restoring such control (immunosurveillance) or at least establish an equilibrium state that slows down disease progression. This is true not only for immunotherapies, such as immune checkpoint inhibitors (ICIs), but also for conventional chemotherapy, targeted anticancer agents, and radiation therapy.

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Article Synopsis
  • Salivary gland cancers (SGCs) are rare and aggressive, often lacking effective treatments when they spread, prompting a phase 2 trial of nivolumab and ipilimumab in 64 metastatic SGC patients.
  • Results showed some success in "other SGCs" cohort (16% response) but limited efficacy in adenoid cystic carcinoma (6% response), with notable adverse events occurring in 38% of patients.
  • Genetic and immune cell analyses indicated that responding tumors had active T cell responses and certain neoantigens, suggesting a potential path for treatment in non-ACC SGCs like salivary duct carcinomas.
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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple cancer types. However, only a fraction of patients with cancer responds to ICIs employed as stand-alone therapeutics, calling for the development of safe and effective combinatorial regimens to extend the benefits of ICIs to a larger patient population. In addition to exhibiting a good safety and efficacy profile, targeted radionuclide therapy (TRT) with radiopharmaceuticals that specifically accumulate in the tumor microenvironment has been associated with promising immunostimulatory effects that (at least in preclinical cancer models) provide a robust platform for the development of TRT/ICI combinations.

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  • Recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) has poor survival rates and limited effectiveness of immune checkpoint blockade (ICB) therapies, with current biomarkers like tumor mutational burden (TMB) offering only modest predictive value.
  • A study of 133 ICB-treated patients identified 6 distinct molecular subtypes of HNSCC tumors, which showed varied response rates to treatment and were separately validated in another patient group.
  • Researchers developed a predictive model using clinical and genomic features that more accurately forecasted patient outcomes compared to TMB alone, establishing a tool that can improve risk stratification for patients eligible for ICB treatment.
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  • Hürthle cell carcinoma (HCC) is a rare thyroid cancer with a tendency for metastasis, poor treatment options, and unfavorable outcomes, necessitating a better understanding of its immune features and responses to therapies.
  • RNA sequencing of HCC tumors revealed low immune infiltration and a link between tumor genetic characteristics like mutation burden and immune activity, with aggressive forms showing even less immune presence.
  • The study identified specific immune vulnerabilities related to HCC recurrence, highlighting how genetic alterations and metabolic changes contribute to an immune-depleted environment in these tumors.
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  • Genetic alterations in diffuse gliomas, like NFKBIA deletions, help indicate clinical behavior, although some variability persists.
  • NFKBIA haploinsufficiency is linked to worse patient outcomes and distinct genetic patterns, especially at tumor recurrence.
  • The presence of NFKBIA deletions can predict shorter survival in IDH mutant glioma patients, highlighting the need to include this factor in prognostic models.
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Over the past decade, the emergence of effective immunotherapies has revolutionized the clinical management of many types of cancers. However, long-term durable tumour control is only achieved in a fraction of patients who receive these therapies. Understanding the mechanisms underlying clinical response and resistance to treatment is therefore essential to expanding the level of clinical benefit obtained from immunotherapies.

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Intratumoral heterogeneity is a defining hallmark of glioblastoma, driving drug resistance and ultimately recurrence. Many somatic drivers of microenvironmental change have been shown to affect this heterogeneity and, ultimately, the treatment response. However, little is known about how germline mutations affect the tumoral microenvironment.

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Purpose: Immune checkpoint blockade (ICB) therapy has significantly improved clinical outcomes in bladder cancer. Identification of correlates of benefit is critical to select appropriate therapy for individual patients.

Methods: To reveal genetic variables associated with benefit from ICB, we performed whole-exome sequencing on tumor specimens from 88 patients with advanced bladder cancer treated with ICB.

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In cancer, evolutionary forces select for clones that evade the immune system. Here we analyzed >10,000 primary tumors and 356 immune-checkpoint-treated metastases using immune dN/dS, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, to measure immune selection in cohorts and individuals. We classified tumors as immune edited when antigenic mutations were removed by negative selection and immune escaped when antigenicity was covered up by aberrant immune modulation.

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FAT atypical cadherin 1 (FAT1), a transmembrane protein, is frequently mutated in various cancer types and has been described as context-dependent tumor suppressor or oncogene. The FAT1 gene is mutated in 12-16% of T-cell acute leukemia (T-ALL) and aberrantly expressed in about 54% of T-ALL cases contrasted with absent expression in normal T-cells. Here, we characterized FAT1 expression and profiled the methylation status from T-ALL patients.

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Unlabelled: Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation.

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Background: Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance.

Methods: Here, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC.

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Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance.

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Tumors are populated by antigen-presenting cells (APCs) including macrophage subsets with distinct origins and functions. Here, we examined how cancer impacts mononuclear phagocytic APCs in a murine model of breast cancer. Tumors induced the expansion of monocyte-derived tumor-associated macrophages (TAMs) and the activation of type 1 dendritic cells (DC1s), both of which expressed and required the transcription factor interferon regulatory factor-8 (IRF8).

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Background: Merkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (~80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens.

Methods: A patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy.

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