Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer

Abstract

BackgroundDespite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer.MethodsThis study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort.ResultsIn the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well.ConclusionsOur results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs.

Tumor immune microenvironment-based classifications of bladder cancer for enhancing the response rate of immunotherapy

“…In addition, Lu et al. 53 revealed that patients treated with immune checkpoint blockade therapy could receive a durable clinical benefit and achieve better survival if they exhibited a lower CNA burden. Gene mutation is another key component upon which we focused with respect to the three immunophenotypes.…”

Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

“…30 Several studies have indicated that CNVs identified in tumor tissue is related to the response to immunotherapy in patients with cancer. [31][32][33][34] A recent study found that HCC tumors with a low burden of broad copy number chromosomal alterations display higher immune infiltration and have a better response rate to anti-PD-1 inhibitors than those with a median/high broad copy number. 35 Moreover, Davoli et al 31 found that a higher CNV burden in tumor tissue correlated with immune escape and poorer survival in patients with metastatic melanoma treated with immunotherapy.…”

Hypoxia and the phenomenon of immune exclusion

“…Davoli et al (2017) performed a bioinformatic analysis on 5255 tumor and normal samples representing 12 cancer types and found that reduced expression of markers for cytotoxic immune cell infiltrates was correlated with high levels of SCNAs [300]. Recently, further bioinformatic studies in different types of cancers confirmed that elevated levels of SCNAs are correlated with a decreased immune signature or an increase in pathways referring to immune suppression [301][302][303]. As mentioned in the previous chapter, hypoxia is responsible for a moderate genome instability, due to the transcriptional and translational repression of genes involved in DNA damage repair pathways.…”