Because of the unique tumor microenvironment (TME), immunotherapy and targeted therapies have shown limited efficacy in treating pancreatic adenocarcinoma (PAAD). CD8 + T cells play crucial roles in regulating the TME in PAAD; therefore, exploring the function of CD8 + T-cell-related genes (CD8RGs) in PAAD has high potential clinical value and could provide a comprehensive understanding of the microenvironment of PAAD. We employed the weighted gene coexpression network analysis and CIBERSORT algorithms to assess PAAD transcriptome data from The Cancer Genome Atlas (TCGA) dataset and identify modules strongly associated with CD8 + T cell infiltration. Using least absolute shrinkage and selection operator regression analysis and Kaplan–Meier curves, we developed a prognostic risk score model for patients with PAAD. We validated this model using single-cell and transcriptome datasets obtained from the Gene Expression Omnibus (GEO). We also examined the correlations between the risk score and factors such as the TME, clinical characteristics, and tumor mutation burden (TMB). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed on differentially expressed genes between the high- and low-risk groups. In addition, the Tumor Immune Dysfunction and Exclusion website and “pRRophetic” R package were used to predict response to immunotherapy and chemotherapy in the high- and low-risk groups, respectively. Finally, we analyzed the expressions of hub genes at the cellular level with quantitative real-time PCR. A risk model based on five CD8RGs was established and validated using TCGA and GEO datasets. The low-risk group exhibited significantly longer overall and progression-free survival. A positive correlation between the TMB and the risk score was observed. The TME analysis revealed a significant correlation between the risk score and immune function, as well as immune checkpoints. The expression of hub genes was significantly correlated with the infiltration level of CD8 + T cells. The high-risk group responded better to immunotherapy, paclitaxel, cisplatin, mitomycin C, afatinib (BIBW2992), and gefitinib. In contrast, the low-risk group showed higher sensitivity to sunitinib, MK.2206, palbociclib (PD.0332991), and axitinib. Compared with that in normal pancreatic epithelial cells, the expression levels of BCL11A, PHOSPHO1, and GNG7 were significantly decreased, while those of KLK11 and VCAM1 were significantly increased in pancreatic tumor cells. CD8RGs play an important role in regulating the TME of PAAD. Five hub genes—BCL11A, KLK11, GNG7, PHOSPHO1, and VCAM1—are closely associated with the prognosis of PAAD patients, providing new references for the exploration of biomarkers. Furthermore, our findings offer novel insights for clinical decision-making.

Abstract Background Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non–small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC. Methods Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained. Results A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group. Conclusion Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.

BACKGROUND:Immune checkpoint inhibitors (ICIs), especially those targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), have introduced a new treatment landscape for many types of tumors. However, they only achieve a limited therapeutic response. Hence, identifying patients who may benefit from ICIs is currently a challenge.METHODS:47 tumor patients harboring ARID1A mutations were retrospectively studied. The genomic profiling data through next-generation sequencing (NGS) and relevant clinical information were collected and analyzed. Additionally, bioinformatics analysis of the expression of immune checkpoints and immune cell infiltration levels was conducted in ARID1A-mutant gastric cancer (GC).RESULTS:ARID1A mutations frequently co-occur with mutations in DNA damage repair (DDR)-associated genes. Among the 35 ARID1A-mutant patients who received immunotherapy, 27 were evaluable., with the objective response rate (ORR) was 48.15% (13/27), and the disease control rate (DCR) was 92.59% (25/27). Moreover, survival assays revealed that ARID1A-mutant patients had longer median overall survival (mOS) after immunotherapy. In ARID1A-mutated GC patients, receiving ICIs treatment indicated longer progressive-free survival (PFS). Additionally, the incidence of microsatellite instability-high (MSI-H), high tumor mutation burden (TMB-H) and Epstein‒Barr virus (EBV) infection was elevated. Bioinformatic analysis showed significant enrichment of immune response and T cell activation pathway within differentially expressed genes in ARID1A-mutant GC group. Finally, ARID1A mutations status was considered to be highly correlated with the level of tumor infiltrating lymphocytes (TILs) and high expression of immune checkpoints.CONCLUSIONS:Patients with tumors harboring ARID1A mutations may achieve better clinical outcomes from immunotherapy, especially in GC. ARID1A mutations can lead to genomic instability and reshape the tumor immune microenvironment (TIME), which can be used as a biomarker for immunotherapy.

In 2022 ASCO, we reported that the anlotinib–pembrolizumab combination showed promising efficacy and favorable safety as treatment for refractory or recurrent high-grade serous ovarian cancer (HGSOC). The ARID1A are potential biomarkers for predicting the efficacy of this novel regimen. As a continuation of the study, we have updated the data here. Patients with refractory or recurrent HGSOC randomly received pembrolizumab (200 mg, intravenously over 60 min, once every 3 weeks) plus anlotinib (12 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) therapy or pembrolizumab (200 mg, intravenously over 60 min, once every 3 weeks) monotherapy, respectively. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The relationships of potential biomarkers with clinical efficacy were also evaluated, and the tumor environment has been analyzed here. A total of 75 patients were enrolled, with 30 participants receiving the anlotinib-pembrolizumab combination regime and 35 with pembrolizumab monotherapy, respectively. Grade 3 treatment-related adverse events (TRAEs) were recorded in 5 participants (16.7%) who received the combination treatment and 3 (8.6%) in the pembrolizumab monotherapy group, respectively. The PFS was 8.0 months and 4.3 months in the anlotinib-pembrolizumab combination regime and pembrolizumab mono-treatment, respectively. In the anlotinib-pembrolizumab combination treatment group, patients with ARID1A mutation indicated a significant survival benefit compared to patients with the wide type (PFS: 12.5 vs 7.0, P = 0.004). The tumor environment analysis by single-cell sequencing indicated that the anlotinib increased the expression of CD4+T and enhanced the susceptibility of patients to pembrolizumab. The anlotinib-pembrolizumab combination showed promising efficacy and favorable safety as a treatment for refractory or recurrent HGSOC. The ARID1A are potential biomarkers for predicting the efficacy of this novel regimen. Anlotinib could enhance the efficacy of pembrolizumab in refractory or recurrent HGSOC by regulating the tumor microenvironment.

Ferroptosis is a relatively new form of programmed cell death, which can enhance the efficacy of tumor immunotherapy by regulating the tumor microenvironment (TME). In the face of the dilemma of a great difference in the efficacy of immunotherapy for gastric cancer (GC) patients, the exploration of ferroptosis may assist us in predicting immunotherapy efficacy prior to treatment. The potential role of ferroptosis in TME still needs further elucidation. Based on ferroptosis-related genes (FRGs), we systematically evaluated ferroptosis molecular subtypes in gastric cancer. Additionally, the association between these molecular subtypes and the characteristics of TME was examined. A ferroptosis score was constructed to further explore the predictive efficacy of ferroptosis on the immunotherapy response in gastric cancer. There were also 32 other cancers that were evaluated. Three molecular subtypes of ferroptosis in gastric cancer were identified. The three immunophenotypes of tumor immune inflamed, immune excluded, as well as immune desert were mostly in agreement with the TME features of these three subtypes. The individual tumor genetic variation, TME characteristics, immunotherapy response, and prognosis could be assessed by a ferroptosis score. High ferroptosis scores in gastric cancer suggest stromal activation and immunosuppression. It is noted that tumors with a low ferroptosis score are characterized by extensive tumor mutations as well as an immune activation, which are associated with an enhanced immunotherapy response and an improved prognosis. This study reveals that ferroptosis plays an integral role in the regulation of the tumor immune microenvironment. The ferroptosis score may serve as an independent prognostic factor for GC and will deepen our understanding of the TME infiltration mechanisms as well as lead to more rational immunotherapy regimens.