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Predicting the Abscopal Effect: Associated Tumor Histologic Subtypes and Biomarkers.

ABSTRACT: Radiotherapy is a pillar of cancer treatment, which has historically been used primarily to treat localized disease with curative intent. With the increasing role of radiotherapy for metastatic disease and rapid integration of immunotherapy into the standard of care for various cancers, it has been observed that local radiation to one malignant site can lead to shrinkage of tumors at other sites, a phenomenon termed the "abscopal effect." Historically, there was little mechanistic elucidation as to how this phenomenon occurs. However, multiple groups have recently identified associated immuno-prognostic factors, such as high post-radiotherapy absolute lymphocyte count, neoantigens, myeloid-derived suppressor cells, and NK cells. The concomitant use of immunotherapy with radiotherapy has been documented to induce the abscopal effect. As immunotherapies continue to be incorporated into most cancer treatment approaches, understanding which patients are more likely to benefit from an abscopal effect may allow for optimization of both systemic and radiotherapeutic strategies. This review highlights the tumor histologic subtypes and biomarkers of the greatest utility for the recognition and identification of patients likely to benefit from the abscopal effect.

SUBMITTER: Nelson BE

PROVIDER: S-EPMC10233357 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Predicting the Abscopal Effect: Associated Tumor Histologic Subtypes and Biomarkers.

Nelson Blessie Elizabeth BE Adashek Jacob J JJ Sheth Aakash Akshay AA Subbiah Vivek V

Molecular cancer therapeutics 20230601 6

Radiotherapy is a pillar of cancer treatment, which has historically been used primarily to treat localized disease with curative intent. With the increasing role of radiotherapy for metastatic disease and rapid integration of immunotherapy into the standard of care for various cancers, it has been observed that local radiation to one malignant site can lead to shrinkage of tumors at other sites, a phenomenon termed the "abscopal effect." Historically, there was little mechanistic elucidation as ...[more]

PMID: 37259805

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Project description:IntroductionThe purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD).MethodsWe identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic [LEP], acinar or papillary [ACI/PAP], and micropapillary or solid [MIP/SOL]). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection.ResultsMIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049).ConclusionsThese results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.

Project description:Exposure to cigarette smoke creates a field of injury throughout the entire respiratory tract inducing genomic alterations that lead to an “at-risk” airway where and lung cancers develop. Lung squamous cell carcinoma (SCC) arises in the epithelial layer of the bronchial airways and is often preceded by the development of premalignant lesions(PMLs). The presence of high-grade persistent or progressive PMLs is a marker of increased lung cancer risk both at the lesion site elsewhere in the lung. Effective tools to identify and treat premalignant lesions at highest risk of progression to invasive carcinoma are lacking. We profiled via RNA-Seq airway brushing and biopsies (divided into two cohorts: discovery and validation) obtained from high-risk smokers undergoing lung cancer screening via serial auto-fluorescence bronchoscopy procedures. We identified four distinct molecular subtypes (Proliferative, Inflammatory, Secretory, and Normal) in the bronchial biopsies that correspond to a spectrum of biological and morphological alterations. The Proliferative subtype was enriched with dysplastic PMLs from current smokers that exhibit up-regulation of KRT5 and KI67 as well as metabolic and cell cycle pathways, and down-regulation of cilium-associated processes and FOXJ1 expression. Molecular subtype classification in the validation cohort biopsies replicated these significant clinical and biological associations. Airway brushes from normal fluorescing areas of the large airway classified as the Proliferative subtype specifically predicts the presence of biopsies of this same subtype. Within the Proliferative subtype, genes associated with interferon signaling and antigen processing and presentation were observed to be down-regulated among dysplastic biopsies that persistent or progress in the future. Innate and adaptive immune cells were computationally predicted to be depleted in these biopsies and this was confirmed via immunofluorescence staining of adjacent biopsies. These findings provide a proof of concept that molecular biomarkers of endobronchial biopsies can enhance histopathological grading and that immunoprevention strategies are an important future direction in intercepting the progression of PMLs to lung cancer.

Dataset Information

Predicting the Abscopal Effect: Associated Tumor Histologic Subtypes and Biomarkers.

Publications

Predicting the Abscopal Effect: Associated Tumor Histologic Subtypes and Biomarkers.

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