Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity

Abstract

Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.

Integrating circulating-free DNA (cfDNA) analysis into clinical practice: opportunities and challenges

“…The tumour microenvironment can also provide important clues as to how an individual tumour and patient may respond to immunotherapy. Recently, this has included the T-cell receptor (TCR) repertoire of tumour-infiltrating lymphocytes [ 81 – 83 ]. TCR repertoire diversity in peripheral blood prior to treatment initiation could also represent a predictive biomarker to guide the use of immunotherapy [ 84 , 85 ].…”

Indoleamine 2,3-Dioxygenase Immune Status as a Potential Biomarker of Radioiodine Efficacy for Advanced Distant Metastatic Differentiated Thyroid Cancer

“…Evaluation of other available tissue biomarkers, such as sodium iodine transporter, requires adequate samples that can only be obtained in an invasive manner, and is hindered by spatial and temporal heterogeneity. These data underline the challenge to identify a reliable biomarker among the systemic immune components with a clear predictive value for DTC patients, since the development and maintenance of an immune microenvironment has shown clear associations with individual outcome ( 47 ).…”

Identification of Novel Molecular Subgroups in Esophageal Adenocarcinoma to Predict Response to Neo-Adjuvant Therapies

“…Therefore, we used CIBERSORTx cell sorting technology to analyze the RNA sequencing data to compare the cellular composition of the tissues of complete responders to that of poor responders. In another study, CIBERSORTx showed that a subset of patients with advanced solid cancers, characterized by early-on increase of T follicular helper cells after treatment with pembrolizumab immunotherapy, had a favorable progression-free survival [ 27 ]. The main differences that we found were more activated CD4 memory T-cells and neutrophils in responders.…”