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Retrospective data support overall survival (OS) advantage to high clonal tumor mutation burden (cTMB), high clonal neoantigen load (cNEO) and low intratumor heterogeneity (ITH) in cancer patients who receive immunotherapy. In order to explore this relationship prospectively with Vigil, a triple function targeted immunotherapy involving ovarian cancer patients in long term follow up of the Phase 2b VITAL trial, we developed an exome sequencing procedure and associated bioinformatics pipeline to determine clonal signal patterns. DNA libraries containing exome sequences tagged with unique molecular identifiers (UMI) were prepared from paired samples and sequenced on Illumina sequencers to high coverage depths of ~ 930X (tumor) and ~ 130X (normal). Raw sequence reads were processed into optimized binary alignment map (BAM) files, using the UMI information. The BAM files were inputted into modules for calling MHC-I alleles, annotating single nucleotide variants (SNVs) and small insertions/deletions (InDels), and for determination of allelic copy number. The outputs were used to predict the sequence of peptide neoantigens and to perform clonality analysis in order to assign each SNV and InDel in a patient tumor sample to a primary clone or subclone. The Clonal Neoantigen pipeline was further assessed using whole exome Illumina sequencing data from three previously published studies. Evaluation of the pipeline using synthetic sequencing data from a sub-clonal deconvolution tool benchmarking study, showed positive predictive value (PPV) and positive percent agreement (PPA) of > 97.5% and > 96.5%, respectively, for SNV and InDel detection with minimum requirements for variant density and allele fraction. Haplotype calls from the Clonal Neoantigen pipeline MHC-I/ MHC-II typing module matched a published benchmark for 91.5% of the calls in a sample of 99 patients. Analysis of exome sequencing data from 14 patients with advanced melanoma revealed a strong correlation between cTMB values determined by the Clonal Neoantigen pipeline as compared to those calculated from the published data (R 2  = 0.99). Following validation, the wet lab process and Clonal Neoantigen pipeline was applied to a set of matched normal, tumor, and Vigil product samples from 9 (n = 27 samples) ovarian cancer subjects entered into the VITAL (CL-PTL-119) trial. Results demonstrated marked correlation (R 2  = 0.98) of cTMB between tumor used to construct Vigil and Vigil product. Correlation between tumor and Vigil for the cNEO and ITH metrics, showed R 2 values of 0.95 and 0.87, respectively. The consistency of the Clonal Neoantigen pipeline results with previously published data as well as the agreement between results for tumor and Vigil for the entire system provide a strong basis of support for utilization of this pipeline for prospective determination of cTMB, cNEO, and ITH values in clinical tumor tissue in order to explore possible correlative relationships with clinical response parameters.

Introduction The use of pembrolizumab in patients with microsatellite instability‐high (MSI‐high) and tumor mutation burden‐high (TMB‐high) prostate cancer in Japan is not widely reported. Here, we report the case of a patient with MSI‐high and TMB‐high prostate cancer who responded well to pembrolizumab after multiple systemic treatments. Case Presentation A 68‐year‐old Japanese man was diagnosed with cT4N1M1a prostate cancer. He was treated with several androgen receptor signaling inhibitors and chemotherapy. After intense systemic treatment, disease progression was confirmed, and genomic testing detected MSI‐high and TMB‐high. However, treatment with pembrolizumab resulted in marked prostate‐specific antigen reduction and significant shrinkage of metastases. Conclusion Genomic tests should be considered for high‐grade tumors. MSI‐high and TMB‐high prostate cancer responded well to pembrolizumab in this case, but patients should be carefully monitored for the development of side effects after administration of pembrolizumab.

Although -mutated patients generally do not benefit from checkpoint inhibitors (ICIs), some patients in the KEYNOTE-001 study consistently benefited from this treatment. This study investigated immune microenvironment characteristics to identify the subgroup of patients that may benefit from ICIs. Using data from The Cancer Genome Atlas Program (TCGA) and Cancer Proteome Atlas, TMB and protein level of PD-L1 were explored in the patients with mutations and wild-type patients. Different patterns of mutations (according to EGFR co-mutation with different downstream pathway genesets) were used to group mutation population. Estimated infiltration analyses were used to explore changes in the immune microenvironment. This study analyzed somatic mutation data from 1287 patients from five cohorts (TCGA, Broad, The Tumour Sequencing Project, Memorial Sloan Kettering Cancer Center, Catalogue Of Somatic Mutations In Cancer database). The probability of mutation was approximately 14.30% (184/1287) and the co-mutation rate was 11.41% (21/184) in patients with mutations. Glycosaminoglycan-related pathways were significantly upregulated in the mutant group. -mutated patients had lower TMB and PD-L1 protein levels than those in wild-type patients. Increase immature DCs infiltration and decreased NK CD56dim, T gamma delta, cytotoxic, and Th2 cell infiltration were the main immune changes in -mutated patients. Patients with -MAPK co-mutations had higher levels of TMB and PD-L1 protein expression. Meanwhile, the co-mutated patients had a similar immune microenvironment as that in wild-type patients. In this study, we defined a subgroup of patients with -MAPK co-mutations. These co-mutated patients may benefit from ICI treatment.

Immune checkpoint blockade (ICB) therapy has achieved remarkable clinical benefit in non‐small‐cell lung cancer (NSCLC), but our understanding of biomarkers that predict the response to ICB remain obscure. Here we integrated somatic mutational profile and clinicopathologic information from 113 NSCLC patients treated by ICB (CTLA‐4/PD‐1). High tumor mutation burden (TMB) and neoantigen burden were identified significantly associated with improved efficacy in NSCLC immunotherapy. Furthermore, we identified apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like (APOBEC) mutational signature was markedly associated with responding of ICB therapy (log‐rank test, P = .001; odds ratio (OR), 0.18 [95% CI, 0.06‐0.50], P < .001). The association with progression‐free survival remained statistically significant after controlling for age, sex, histological type, smoking, PD‐L1 expression, hypermutation, smoking signature and mismatch repair (MMR) (HR, 0.30 [95% CI, 0.12‐0.75], P = .010). Combined high TMB with APOBEC signature preferably predict immunotherapy responders in NSCLC cohort. The CIBERSORT algorithm revealed that high APOBEC mutational activity samples were associated with increased infiltration of CD4 memory activated T cells, CD8+ T cells and natural killer (NK) cells, but reduced infiltration of regulatory T cells. Besides, individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, the PTEN mutation was only found in non‐responders (Fisher's exact test, all P < .05). These findings may be applicable for guiding immunotherapy for patients with NSCLC. Multivariate analysis of APOBEC mutational signature is strongly associated with objective immune response and progression‐free survival in immunotherapy, but not identified in conventional chemotherapy of the Cancer Genome Atlas (TCGA) samples, suggesting the specific predictive effects of ICB treatment. High APOBEC mutational activity samples were enriched for immune checkpoint gene markers and tumor immune lymphocyte infiltration makers. Combined TMB with an APOBEC signature may preferably predict NSCLC immunotherapy responders. Individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, PTEN was only noticed in non‐responders.

Cuproptosis is a copper-dependent cell death mechanism that is associated with tumor progression, prognosis, and immune response. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of triple-negative breast cancer (TNBC) remains unclear. In total, 346 TNBC samples were collected from The Cancer Genome Atlas database and three Gene Expression Omnibus datasets, and were classified using R software packages. The relationships between the different subgroups and clinical pathological characteristics, immune infiltration characteristics, and mutation status of the TME were examined. Finally, a nomogram and calibration curve were constructed to predict patient survival probability to improve the clinical applicability of the CRG_score. We identified two CRG clusters with immune cell infiltration characteristics highly consistent with those of the immune-inflamed and immune-desert clusters. Furthermore, we demonstrated that the gene signature can be used to evaluate tumor immune cell infiltration, clinical features, and prognostic status. Low CRG_scores were characterized by high tumor mutation burden and immune activation, good survival probability, and more immunoreactivity to CTLA4, while high CRG_scores were characterized by the activation of stromal pathways and immunosuppression. This study revealed the potential effects of CRGs on the TME, clinicopathological features, and prognosis of TNBC. The CRGs were closely associated with the tumor immunity of TNBC and are a potential tool for predicting patient prognosis. Our data provide new directions for the development of novel drugs in the future.

Although the clinical development of immune checkpoint inhibitors (ICIs) therapy has ushered in a new era of anti-tumor therapy, with sustained responses and significant survival advantages observed in multiple tumors, most patients do not benefit. Therefore, more and more attention has been paid to the identification and development of predictive biomarkers for the response of ICIs, and more in-depth and comprehensive understanding has been continuously explored in recent years. Predictive markers of ICIs efficacy have been gradually explored from the expression of intermolecular interactions within tumor cells to the expression of various molecules and cells in tumor microenvironment, and been extended to the exploration of circulating and host systemic markers. With the development of high-throughput sequencing and microarray technology, a variety of biomarker strategies have been deeply explored and gradually achieved the process from the identification of single marker to the development of multifactorial synergistic predictive markers. Comprehensive predictive-models developed by integrating different types of data based on different components of tumor-host interactions is the direction of future research and will have a profound impact in the field of precision immuno-oncology. In this review, we deeply analyze the exploration course and research progress of predictive biomarkers as an adjunctive tool to tumor immunotherapy in effectively identifying the efficacy of ICIs, and discuss their future directions in achieving precision immuno-oncology.

Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be determined using different approaches based on next-generation sequencing. In the case of high values, it indicates a potential response to immunotherapy. In this systematic review, we assessed the potential predictive role of high-TMB in pancreatic ductal adenocarcinoma (PDAC), as well as the histo-molecular features of high-TMB PDAC. High-TMB appeared as a rare but not-negligible molecular feature in PDAC, being present in about 1.1% of cases. This genetic condition was closely associated with mucinous/colloid and medullary histology (p < 0.01). PDAC with high-TMB frequently harbored other actionable alterations, with microsatellite instability/defective mismatch repair as the most common. Immunotherapy has shown promising results in high-TMB PDAC, but the sample size of high-TMB PDAC treated so far is quite small. This study highlights interesting peculiarities of PDAC harboring high-TMB and may represent a reliable starting point for the assessment of TMB in the clinical management of patients affected by pancreatic cancer.

BackgroundLung adenocarcinoma (LUAD) is a common pulmonary malignant disease with a poor prognosis. There were limited studies investigating the influences of the tumor immune microenvironment on LUAD patients’ survival and response to immune checkpoint inhibitors (ICIs). MethodsBased on TCGA-LUAD dataset, we constructed a prognostic immune signature and validated its predictive capability in the internal as well as total datasets. Then, we explored the differences of tumor-infiltrating lymphocytes, tumor mutation burden, and patients’ response to ICI treatment between the high-risk score group and low-risk score group.ResultsThis immune signature consisted of 17 immune-related genes, which was an independent prognostic factor for LUAD patients. In the low-risk score group, patients had better overall survival. Although the differences were non-significant, patients with low-risk scores had more tumor-infiltrating follicular helper T cells and fewer macrophages (M0), which were closely related to clinical outcomes. Additionally, the total TMB was markedly decreased in the low-risk score group. Using immunophenoscore as a surrogate of ICI response, we found that patients with low-risk scores had significantly higher immunophenoscore.ConclusionThe 17-immune-related genes signature may have prognostic and predictive relevance with ICI therapy but needs prospective validation.

POLE and POLD1 encode the catalytic and proofreading subunits of DNA polymerase ε and polymerase δ, and play important roles in DNA replication and proofreading. POLE/POLD1 exonuclease domain mutations lead to loss of proofreading function, which causes the accumulation of mutant genes in cells. POLE/POLD1 mutations are not only closely related to tumor formation, but are also a potential molecular marker for predicting the efficacy of immunotherapy in pan-carcinomatous species. The association of POLE/POLD1 mutation, ultra-high mutation load, and good prognosis have recently become the focus of clinical research. This article reviews the function of POLE/POLD1 , its relationship with deficient mismatch repair/high microsatellite instability, and the role of POLE/POLD1 mutation in the occurrence and development of various tumors.

A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.