Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Abstract

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Coming in from the cold: overcoming the hostile immune microenvironment of medulloblastoma

“…A high tumor mutation burden has been suggested to contribute to immunogenicity and to predict response to immunotherapy. Concordantly, a recent study has found a sustained response to anti-PD-1 therapy in pediatric cancer patients with an exceptionally high load of mutations and microsatellite insertion–deletion events due to germline DNA mismatch repair deficiency or polymerase proofreading deficiency ( Das et al 2022 ). However, this correlation found in ultrahypermutated tumors does not necessarily extrapolate to other cancers, as recently shown by a large-scale study by Touat et al (2020) .…”

eIF6 is potential diagnostic and prognostic biomarker that associated with 18F-FDG PET/CT features and immune signatures in esophageal carcinoma

“…By combining contrast-enhanced CT images and RNA-seq genomic data from tumour biopsies, Roger et al demonstrated that imaging biomarker could be useful in estimating CD8 cell count and predicting clinical outcomes of patients treated with anti-PD-1 and PD-L1[ 49 ]. The dual roles of mutation burden and MS-indels was identified in predicting outcomes of central nervous system and synchronous cancers following immune checkpoint inhibitors (ICIs) treatment [ 50 ]. Thus, analysis of the cancer-specific immune biomarkers may reveal novel molecular targets for ESCA treatment.…”

KDELR1 Is an Independent Prognostic Predictor and Correlates With Immunity in Glioma

“…Recently, with the rapid advances in next-generation technology, research on the biomolecular markers and associated signaling pathways that are involved in the occurrence and development of gliomas has made substantial progress (38). After the IDH mutation status was confirmed to be related to the prognosis of patients with GBMs, a subsequent study reported that the chromosome 1p/19q codeletion status, O6-methylguanine-DNA methyltransferase (MGMT) promoter region genotype, a-thalassemiamental retardation syndrome X (ATRX), and amplification of the epidermal growth factor receptor (EGFR) played more important roles in the prognosis and treatment prediction of gliomas (39,40). Our study demonstrates that KDELR1 is downregulated in the 1p/19q codeletion group compared with the 1p/19q non-codeletion group.…”