The coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, has rapidly expanded to a global pandemic. However, numbers of infected cases, deaths, and mortality rates related to COVID-19 vary from country to country. Although many studies were conducted, the reasons of these differences have not been clarified. In this study, we comprehensively investigated 12,343 SARS-CoV-2 genome sequences isolated from patients/individuals in six geographic areas and identified a total of 1234 mutations by comparing with the reference SARS-CoV-2 sequence. Through a hierarchical clustering based on the mutant frequencies, we classified the 28 countries into three clusters showing different fatality rates of COVID-19. In correlation analyses, we identified that ORF1ab 4715L and S protein 614G variants, which are in a strong linkage disequilibrium, showed significant positive correlations with fatality rates (r = 0.41, P = 0.029 and r = 0.43, P = 0.022, respectively). We found that BCG-vaccination status significantly associated with the fatality rates as well as number of infected cases. In BCG-vaccinated countries, the frequency of the S 614G variant had a trend of association with the higher fatality rate. We also found that the frequency of several HLA alleles, including HLA-A*11:01, were significantly associated with the fatality rates, although these factors were associated with number of infected cases and not an independent factor to affect fatality rate in each country. Our findings suggest that SARS-CoV-2 mutations as well as BCG-vaccination status and a host genetic factor, HLA genotypes might affect the susceptibility to SARS-CoV-2 infection or severity of COVID-19.

To control and prevent the current COVID-19 pandemic, the development of novel vaccines is an emergent issue. In addition, we need to develop tools that can measure/monitor T-cell and B-cell responses to know how our immune system is responding to this deleterious virus. However, little information is currently available about the immune target epitopes of novel coronavirus (SARS-CoV-2) to induce host immune responses. Through a comprehensive bioinformatic screening of potential epitopes derived from the SARS-CoV-2 sequences for HLAs commonly present in the Japanese population, we identified 2013 and 1399 possible peptide epitopes that are likely to have the high affinity (<0.5%- and 2%-rank, respectively) to HLA class I and II molecules, respectively, that may induce CD8⁺ and CD4⁺ T-cell responses. These epitopes distributed across the structural (spike, envelope, membrane, and nucleocapsid proteins) and the nonstructural proteins (proteins corresponding to six open reading frames); however, we found several regions where high-affinity epitopes were significantly enriched. By comparing the sequences of these predicted T cell epitopes to the other coronaviruses, we identified 781 HLA-class I and 418 HLA-class II epitopes that have high homologies to SARS-CoV. To further select commonly-available epitopes that would be applicable to larger populations, we calculated population coverages based on the allele frequencies of HLA molecules, and found 2 HLA-class I epitopes covering 83.8% of the Japanese population. The findings in the current study provide us valuable information to design widely-available vaccine epitopes against SARS-CoV-2 and also provide the useful information for monitoring T-cell responses.

Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, from which the majority of patients experienced no or minimum clinical benefit. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer‐specific immune targets. Highly tumor‐specific antigens, neoantigens, are generated by somatic mutations that are not present in normal cells. It is plausible that by targeting antigens with high tumor‐specificity, such as neoantigens, the likelihood of toxic effects is very limited. However, understanding the interaction between neoantigens and the host immune system remains a significant challenge. This review focuses on the potential use of neoantigen‐targeted immunotherapies in cancer treatment and the recent progress of different strategies in predicting, identifying, and validating neoantigens. Successful identification of highly tumor‐specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients.

Perioperative systemic chemotherapy improves the prognosis of upper tract urothelial carcinoma (UTUC). The first objective of this study was to verify whether perioperative circulating tumor DNA (ctDNA) analysis using a pan‐cancer gene panel and next‐generation sequencing could identify patients with poor prognosis who require perioperative chemotherapy. Second, we investigated whether ctDNA is useful for minimal residual disease (MRD) detection and treatment monitoring in UTUC. This study included 50 patients with untreated UTUC, including 43 cases of localized UTUC. We performed targeted ultradeep sequencing of plasma cell‐free DNA (cfDNA) and buffy coat DNA and whole‐exome sequencing of cancer tissues, allowing exclusion of possible false positives. We attempted to stratify the prognosis according to the perioperative ctDNA levels in patients with localized UTUC. In patients with metastatic UTUC, ctDNA was evaluated before, during, and after systemic treatment. In total, 23 (46%) of 50 patients with untreated UTUC were ctDNA positive, and 17 (40%) of 43 patients with localized UTUC were ctDNA positive. Of the detected TP53 mutations, 19% were false positives due to clonal hematopoiesis of indeterminate potential. Among preoperative risk factors, only the preoperative ctDNA fraction>2% was a significant and independent risk factor associated with worse recurrence‐free survival (RFS). Furthermore, the existence of ctDNA early points after the operation was significantly associated with worse RFS, suggesting the presence of MRD. ctDNA also showed a potential as a real‐time marker for systemic therapy in patients with metastatic UTUC. Detection of ctDNA may indicate potential metastasis and guide decisions on perioperative chemotherapy.

Purpose: Squamous cell carcinoma of the head and neck (SCCHN) is a lethal cancer with a suboptimal 5-year overall survival of approximately 50% with surgery and/or definitive chemoradiotherapy. Novel treatments are thus urgently awaited. Immunotherapy with checkpoint blockade has emerged as a promising option for patients with recurrent/metastatic SCCHN; however, it has not been investigated in the curative-intent setting yet. The purpose of this study was to investigate the T-cell receptor repertoire and the tumor microenvironment in tumor tissues of SCCHN patients with locoregionally advanced disease. Experimental Design: We performed T-cell receptor sequencing of tumor tissues from 44 patients with locoregionally advanced SCCHN prior to treatment with definitive chemoradiotherapy and correlated the T-cell clonality and the mRNA expression levels of immune-related genes with clinicopathologic parameters. Results: Clonal expansion of T cells was significantly higher in human papilloma virus (HPV)–negative compared with HPV-positive tumors, signifying more robust antigen presentation in HPV-negative tumors. The latter was supported by the higher percentage of HPV-negative tumors expressing HLA-A protein compared with HPV-positive tumors (P = 0.049). Higher GRZB levels correlated significantly with longer recurrence-free survival (log-rank, P = 0.003) independent of tumor size, nodal stage, and HPV status. Conclusions: Our findings support clonal expansion of T cells in SCCHN patients with locoregionally advanced disease and imply differences in the antigen presentation capacity between HPV-negative and HPV-positive tumors. Elevated GRZB mRNA levels may also serve as a favorable and independent predictor of outcome in SCCHN patients treated with chemoradiotherapy. These data provide rationale for the introduction of immunotherapeutic approaches in the curative-intent setting. Clin Cancer Res; 23(16); 4897–907. ©2017 AACR.