The interplay between neoantigens and immune cells in sarcomas treated with checkpoint inhibition

Frontiers in Immunology

Immunology

Melissa Burgess¹  Hussein A. Tawbi²  Emily Z. Keung³  Ola Myklebost⁴  Leonardo A. Meza-Zepeda⁵  Brandon Malone⁶  Pubudu Samarakoon⁶  Richard Stratford⁶  Ioannis Vardaxis⁶  Trevor Clancy⁶  Hugues Fontenelle⁶  Boris Simovski⁶  Irantzu Anzar⁷ 

[1] Department of Medical Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States;Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Institute for Cancer Research, Oslo University Hospital, Oslo, Norway;Department of Clinical Science, University of Bergen, Bergen, Norway;Institute for Cancer Research, Oslo University Hospital, Oslo, Norway;Genomics Core Facility, Department of Core Facilities, Oslo University Hospital, Oslo, Norway;Oslo Cancer Cluster, NEC OncoImmunity AS, Oslo, Norway;Oslo Cancer Cluster, NEC OncoImmunity AS, Oslo, Norway;Institute of Clinical Medicine, University of Oslo, Oslo, Norway;

关键词: neoantigens;    checkpoint inhibition therapy;    next generation sequencing;    biomarker discovery;    machine learning;    immune escape;   

DOI  :  10.3389/fimmu.2023.1226445

 received in 2023-05-21, accepted in 2023-07-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionSarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes.MethodsTo explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. We used advanced computational methods to investigate key immune properties, such as neoantigens and immune cell composition in the tumor microenvironment (TME).ResultsA multifactorial analysis suggested that expression of high quality neoantigens in the context of specific immune cells in the TME are key prognostic markers of progression-free survival (PFS). The presence of several types of immune cells, including T cells, B cells and macrophages, in the TME were associated with improved PFS. Importantly, we also found the presence of both CD8+ T cells and neoantigens together was associated with improved survival compared to the presence of CD8+ T cells or neoantigens alone. Interestingly, this trend was not identified with the combined presence of CD8+ T cells and TMB; suggesting that a combined CD8+ T cell and neoantigen effect on PFS was important.DiscussionThe outcome of this study may inform future trials that may lead to improved outcomes for sarcoma patients treated with ICI.

【 授权许可】

Unknown   
Copyright © 2023 Anzar, Malone, Samarakoon, Vardaxis, Simovski, Fontenelle, Meza-Zepeda, Stratford, Keung, Burgess, Tawbi, Myklebost and Clancy