Tertiary lymphoid structure patterns predicted anti-PD1 therapeutic responses in gastric cancer

Objective:Recent studies have highlighted the distinct value of tertiary lymphoid structure(TLS)for immunotherapeutic response prediction.However,it remains unclear whether TLS could play such roles in gastric cancer(GC).Methods:In this study,tumor tissue slices from 292 GC patients from Zhongshan Hospital were firstly reviewed to explore the correlation between TLS and clinical characteristics.Subsequently,we curated 38 reported genes that may function as triggers of TLS and performed consensus molecular subtyping in public RNA-seq datasets to determine TLS patterns in GC.Based on the differentially expressed genes acquired from two TLS patterns,we quantified TLS-related genes on the principal component analysis(PCA)algorithm to develop TLS score.A Zhongshan immunotherapy cohort including 13 patients who received programmed cell death 1(PD1)blockade therapy was established to conduct RNA sequencing analysis and multiplex immunohistochemistry(mIHC)tests using formalin-fixed and paraffin-embedded(FFPE)tissues.The corresponding TLS score and immune cell counts were further compared based on therapeutic response variations.Results:Mature TLS was revealed as an independent prognostic factor in 292 GC patients.Patients with higher TLS score was characterized by prolonged survival time and superior response to immunotherapy.TLS score was correlated with immunotherapy-related characters,such as microsatellite instability(MSI)and tumor mutation burden(TMB).In addition,RNA-seq data analysis in the Zhongshan immunotherapy cohort indicated that a higher TLS score was correlated with a superior response to PD1 blockade therapy.mIHC tests also revealed that PD1+CD8+T cell counts were significantly increased in the high-TLS score group.Conclusions:This study highlighted that TLS was significantly associated with immune landscape diversity and complexity.Quantitatively evaluating TLS patterns of individual tumor will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.

Small molecules in targeted cancer therapy:advances,challenges,and future perspectives

Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs,targeted therapeutic drugs have become mainstream cancer treatments.Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration(FDA)in 2001,an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies.By December 2020,89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration(NMPA)of China.Despite great progress,small-molecule targeted anti-cancer drugs still face many challenges,such as a low response rate and drug resistance.To better promote the development of targeted anti-cancer drugs,we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification.We present all the approved drugs as well as important drug candidates in clinical trials for each target,discuss the current challenges,and provide insights and perspectives for the research and development of anti-cancer drugs.