The evolutionary dynamics of tumor-associated neoantigens carry information about drug sensitivity and resistance to the immune checkpoint blockade (ICB). However, the spectrum of somatic mutations is highly heterogeneous among patients, making it difficult to track neoantigens by circulating tumor DNA (ctDNA) sequencing using "one size fits all" commercial gene panels. Thus, individually customized panels (ICPs) are needed to track neoantigen evolution comprehensively during ICB treatment. Dominant neoantigens are predicted from whole exome sequencing data for treatment-naïve tumor tissues. Panels targeting predicted neoantigens are used for personalized ctDNA sequencing. Analyzing ten patients with nonsmall cell lung cancer, ICPs are effective for tracking most predicted dominant neoantigens (80-100%) in serial peripheral blood samples, and to detect substantially more genes (18-30) than the capacity of current commercial gene panels. A more than 50% decrease in ctDNA concentration after eight weeks of ICB administration is associated with favorable progressionfree survival. Furthermore, at the individual level, the magnitude of the early ctDNA response is correlated with the subsequent change in tumor burden. The application of ICP-based ctDNA sequencing is expected to improve the understanding of ICB-driven tumor evolution and to provide personalized management strategies that optimize the clinical benefits of immunotherapies.

Background: Tumor-infiltrating leukocytes (TILs) are immune cells surrounding tumor cells, and several studies have shown that TILs are potential survival predictors in different cancers. However, few studies have dissected the differences between hepatitis B- and hepatitis C-related hepatocellular carcinoma (HBV−HCC and HCV−HCC). Therefore, we aimed to determine whether the abundance and composition of TILs are potential predictors for survival outcomes in HCC and which TILs are the most significant predictors. Methods: Two bioinformatics algorithms, ESTIMATE and CIBERSORT, were utilized to analyze the gene expression profiles from 6 datasets, from which the abundance of corresponding TILs was inferred. The ESTIMATE algorithm examined the overall abundance of TILs, whereas the CIBERSORT algorithm reported the relative abundance of 22 different TILs. Both HBV−HCC and HCV−HCC were analyzed. Results: The results indicated that the total abundance of TILs was higher in non-tumor tissue regardless of the HCC type. Alternatively, the specific TILs associated with overall survival (OS) and recurrence-free survival (RFS) varied between subtypes. For example, in HBV−HCC, plasma cells (hazard ratio [HR] = 1.05; 95% CI 1.00–1.10; p = 0.034) and activated dendritic cells (HR = 1.08; 95% CI 1.01–1.17; p = 0.03) were significantly associated with OS, whereas in HCV−HCC, monocytes (HR = 1.21) were significantly associated with OS. Furthermore, for RFS, CD8+ T cells (HR = 0.98) and M0 macrophages (HR = 1.02) were potential biomarkers in HBV−HCC, whereas neutrophils (HR = 1.01) were an independent predictor in HCV−HCC. Lastly, in both HBV−HCC and HCV−HCC, CD8+ T cells (HR = 0.97) and activated dendritic cells (HR = 1.09) had a significant association with OS, while γ delta T cells (HR = 1.04), monocytes (HR = 1.05), M0 macrophages (HR = 1.04), M1 macrophages (HR = 1.02), and activated dendritic cells (HR = 1.15) were highly associated with RFS. Conclusions: These findings demonstrated that TILs are potential survival predictors in HCC and different kinds of TILs are observed according to the virus type. Therefore, further investigations are warranted to elucidate the role of TILs in HCC, which may improve immunotherapy outcomes.

BackgroundImmune checkpoint inhibitor (ICPi) has become a major treatment in advanced non-small cell lung cancer (NSCLC) and demonstrated a clinical benefit for NSCLC patients with high programmed death ligand-1 (PD-L1) expression without EGFR/ALK/ROS1 drivers; however, the benefit in BRAF V600E NSCLC is so far unknown. Here, we report a case of prolonged tumor response to the combination of immunotherapy with chemotherapy in a non-smoking BRAF V600E NSCLC patient.Materials and MethodsWe verify a co-expression of BRAF V600E mutation and PD-L1 high expression more than 50% on formalin-fixed paraffin-embedded tumor sample of a newly diagnosed lung adenocarcinoma patient by immunohistochemistry and BRAF V600E/EGFR/ALK/ROS1 Mutations Detection Kit. The tissue and liquid biopsies were further subjected to next-generation sequencing (NGS) for identification of mutations with progression on immunotherapy and BRAF inhibitor (BRAFi). The patient had provided written informed consent and authorized the publication of clinical case.ResultsWe demonstrate the case of 62-year-old female non-smoker with high PD-L1 expression and BRAF V600E mutated NSCLC. The progression-free survival (PFS) of first-line combination of atezolizumab with platinum-based chemotherapy and sequential second-line treatment with BRAFi Vemurafenib are 20 and 5.5 months, respectively.ConclusionThis case shows a durable response to ICPi in BRAF V600E non-smoking lung adenocarcinoma with PFS of 20 months under first-line atezolizumab plus chemotherapy treatment. The case supports the idea that the combination immunotherapy may be an attractive option for BRAF V600E mutated non-smoking NSCLC with high PD-L1 expression.

Inter‐individual heterogeneity of the mutational spectrum is the major obstacle of effective in vivo monitoring of mutation‐directed T cell killing by ctDNA sequencing. In article number 1903410, Jianguo Sun, Bo Zhu, and co‐workers develop a customized sequencing strategy that mainly targets predicted neoantigen‐coding mutations. This work significantly broadens the coverage of ctDNA sequencing and is expected to improve personalized management strategies optimizing the clinical benefits of checkpoint immunotherapies.