Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response

Abstract

The resurgence of immune therapies in cancer medicine has elicited a corresponding interest in understanding the basis of patient response or resistance to these treatments. One aspect of patient response clearly lies in the genomic alterations that are associated with cancer onset and progression, including those that contribute to genomic instability and the resulting creation of novel peptide sequences that may present as neoantigens. The immune reaction to these unique ‘non-self’ peptides is frequently suppressed by the tumor itself, but the use of checkpoint blockade therapies, personalized vaccines, or a combination of these treatments may elicit a tumor-specific immune response that results in cell death. Massively parallel sequencing, coupled with different computational analyses, provides unbiased identification of the germline and somatic alterations that drive cancer development, and of those alterations that lead to neoantigens. These range from simple point mutations that change single amino acids to complex alterations, such as frameshift insertion or deletion mutations, splice-site alterations that lead to exon skipping, structural alterations that lead to the formation of fusion proteins, and other forms of collateral damage caused by genome instability that result in new protein sequences unique to the cancer. The various genome instability phenotypes can be identified as alterations that impact DNA replication or mismatch repair pathways or by their genomic signatures. This review provides an overview of current knowledge regarding the fundamentals of genome replication and of both germline and somatic alterations that disrupt normal replication, leading to various forms of genomic instability in cancers, to the resulting generation of neoantigens and, ultimately, to immune-responsive and resistant phenotypes.

Anti-angiogenic Agents in Combination With Immune Checkpoint Inhibitors: A Promising Strategy for Cancer Treatment

“…The results showed that, especially CD16+ and CD68+ cells, were associated with an affirmative response to ICIs, as well as prolonged survival. Subsequent studies including patients with NSCLC or metastatic melanoma receiving ICIs discovered that neoantigens coded by DNA with loss-of-function mutations can result in drug resistance ( 138 – 140 ). Alterations in PD-L1 and PD-L2 copy number ( 141 ), as well as microsatellite instability/mismatch-repair deficiency ( 142 ) were identified as potential predictive biomarkers.…”

Differential Genomic Instability-Associated LncRNAs Predict Differences of Clinical Outcome and Immunity in Left- And Right- Sided Colon Adenocarcinoma

“…Various forms of genomic instability in cancers produce new antigens and immune-responsive phenotypes eventually [14]. In the analysis of LCCs and RCCs, we have con rmed that genomic instability does affect the immune response and the prognosis through a series of potential mechanisms.…”

“…Also, a variety of biological processes are related to genome instability, including abnormal transcription and post-transcriptional regulation, DNA damage regulation, etc [13]. Latest ndings disclosed that variations in the instability of the genome produces new antigens, which affects the immune phenotype and immunotherapy response [14]. Long non-coding RNAs (lncRNAs) are considered to be incapable to encode proteins, and they play an indispensable regulatory role in tumors.…”

Therapy of Primary Liver Cancer

“… 171 , 172 Neoantigens are mostly caused by errors in the DNA replication process of cancer cells, and some are caused by environmental factors such as viruses, radiation, and chemicals. 173 Although personalized tumor vaccines are still in the exploratory stage, the currently reported clinical trials of individualized neoantigen vaccines have shown encouraging results, especially in the treatment of melanoma, with high accuracy and low side effects. 174 , 175 , 176 , 177 , 178 , 179 , 180 …”