Immune Cells In Tumor Tissues Research Articles

Natural killer cell-associated prognosis model characterizes immune landscape and treatment efficacy of diffuse large B cell lymphoma

PurposeNK cells are essential for the detection, identification and prediction of cancer. However, so far, there is no prognostic risk model based on NK cell-related genes to predict the prognosis and treatment outcome of DLBCL patients. This study aimed to explore a risk assessment model that could accurately predict the prognosis and treatment efficacy of DLBCL. MethodsBioinformatics analysis of the expression profiles of DLBCL samples in the GEO database was performed. Cox regression and LASSO regression analysis were used to determine NK cell-related genes associated with patient’s prognosis. Based on these genes, a risk assessment model was constructed to predict the prognosis of patients and the effectiveness of treatment. Finally, qRT-PCR was used to verify the expression of gene tags in clinical samples. ResultsWe identified seven prognosis-related NK cell-related genes (MAP2K1, PRKCB, TNFRSF10B, IL18, LAMP1, RASGRP1, and SP110), and DLBCL patients were divided into low- and high-risk groups based on these genes. Survival analysis showed that the prognosis of patients with low-risk group was better. Pathway enrichment analysis showed that the differentially expressed genes between the two risk groups were related to immune response pathways. Compared with the high-risk group, the low-risk group had higher infiltration of immune cells in tumor tissues. Besides, compared with high-risk group, low-risk patients by immunotherapy or other commonly used anti-tumor drugs might have better efficacy after treatment. In addition, qRT-PCR showed that the expression of risk genes including TNFRSF10B, IL18 and LAMP1 were significantly increased in most DLBCL samples compared to control samples, while the expression of protective genes including MAP2K1, PRKCB, RASGRP1 and SP110 were significantly decreased. ConclusionThe NK cell-related gene signatures were proved to be a reliable indicator of the success of immunotherapy in patients with DLBCL, thus providing a unique evaluation method.

A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer

Despite the groundbreaking impact of immune checkpoint blockade (ICB), response rates in non-small cell lung cancer remain modest, particularly in immune-excluded or immune-desert microenvironments. Toll-like receptor 7 (TLR7) emerges as a latent target bridging innate and adaptive immunity, offering a promising avenue for combination therapies to augment ICB efficacy. Here, we explored the anti-tumor activity of the novel oral TLR7 agonist TQ-A3334 and its potential to enhance anti-programmed death ligand 1 (PD-L1) therapy through a combination strategy in a syngeneic murine lung cancer model. Oral administration of TQ-A3334 significantly alleviated tumor burden in C57BL/6J mice, modulated by type I interferon (IFN), and exhibited low toxicity. This therapy elicited activation of both innate and adaptive immune cells in tumor tissue, particularly increasing the abundance of CD8+ TILs through type I IFN pathway and subsequent CXCL10 expression. In vitro examinations validated that IFN-α-stimulated tumor cells exhibited increased secretion of CXCL10, conducive to the promoted trafficking of CD8+ T cells. Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8+ TIL frequency compared to monotherapy. These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer.

ID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer

Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs) constitute the prominant population of immune cells in tumor tissues, contributing to the formation of CSC niches and a suppressive immune microenvironment. Here, we report that high expression of inhibitor of differentiation 1 (ID1) in TAMs correlates with poor outcome in patients with colorectal cancer (CRC). ID1 expressing macrophages maintain cancer stemness and impede CD8+ T cell infiltration. Mechanistically, ID1 interacts with STAT1 to induce its cytoplasmic distribution and inhibits STAT1-mediated SerpinB2 and CCL4 transcription, two secretory factors responsible for cancer stemness inhibition and CD8+ T cell recruitment. Reducing ID1 expression ameliorates CRC progression and enhances tumor sensitivity to immunotherapy and chemotherapy. Collectively, our study highlights the pivotal role of ID1 in controlling the protumor phenotype of TAMs and paves the way for therapeutic targeting of ID1 in CRC.

ZDHHC9: a promising therapeutic target for triple-negative breast cancer through immune modulation and immune checkpoint blockade resistance

BackgroundTriple-negative breast cancer (TNBC) is a subtype of breast cancer with limited treatment options and poor prognosis. This study aimed to identify potential therapeutic targets based on the expression profiles of differentially expressed genes (DEGs) in TNBC.MethodsThe Limma package was used to identify DEGs in TCGA and GEO datasets. Immunohistochemical (IHC) analysis and western blotting were used to determine the expression of ZDHHC9 in TNBC tissues. Flow cytometry assay and tissue immunofluorescence analysis were used to detect infiltration of multiple immune cells in tumor tissue at different levels of ZDHHC9 expression.ResultsZDHHC9 was identified as a key factor associated with resistance to ICB therapy through weighted gene co-expression network analysis (WGCNA) and single-cell RNA sequencing (scRNA-seq). Subsequently, immunohistochemical (IHC) analysis and western blotting verified that ZDHHC9 expression was elevated in TNBC cancer tissues and that elevated expression of ZDHHC9 was associated with the poor survival of patients with TNBC. Analysis of data from several public datasets revealed that patients with high ZDHHC9 expression had an increased proportion of Ki-67 + breast cancer cells and tended to be basal-like breast cancer. In addition, in vitro and in vivo experiments demonstrated that high expression of ZDHHC9 significantly predicted the efficacy and responsiveness of immunotherapy in TNBC.ConclusionThese findings suggest that ZDHHC9 is a valuable marker for guiding the classification, diagnosis and prognosis of TNBC and developing specific targeted therapies.

Multi-omics analysis revealed the mitochondrial-targeted drug combination to suppress the development of lung cancer.

The incidence and mortality of lung cancer are continuously rising in recent years. Mitochondrial energy metabolism malfunction is found to be crucial in cancer proliferation and bioenergetic reprogramming, especially for lung cancer. In this study, we attempted to use mitochondrial-targeted drug therapy to change the energy metabolism pattern of cancer cells to inhibit the development of lung cancer, and investigated its mechanism of action and key targets through multi-omics studies. In this study, we established the in vivo tumor mouse mode, treated mice with multiple mitochondrial-targeted drug combinations and DDP, severally. Then, we investigated the differences between the 7-drug group with the control group and the DDP treatment group by transcriptomics, proteomics and metabolomics to find the therapeutic targets. We found that mitochondria-targeting drug cocktail therapy, especially the 7-drug regimen, effectively improved mitochondrial metabolism, changed energy supply patterns in lung cancer cells, significantly increased NK cells in tumor tissues, and decreased tumor markers in plasma. Multi-omics analysis informed that the combination of 7-drug could up-regulate mitochondrial oxidative phosphorylation, ATP synthesis and autophagy related genes, and down-regulate proliferation and immune-related genes compared with the control group. By further mapping the protein interaction network, we identified a key target for 7-drug therapy to reverse tumor metabolic reprogramming and validated it in metabolomics. Mitochondrial-targeted drug cocktail therapy can effectively inhibit the occurrence and development of tumors, through the reprogramming of energy metabolism and the increase in immune cells in tumor tissues. Thus, we provide a novel approach for the treatment of lung cancer and present evidence-based clues for the combined use of targeted mitochondrial drugs.

Multiplex Immunohistochemical Analysis of the Spatial Immune Cell Landscape of the Tumor Microenvironment.

The immune cell landscape of the tumor microenvironment potentially contains information for the discovery of prognostic and predictive biomarkers. Multiplex immunohistochemistry is a valuable tool to visualize and identify different types of immune cells in tumor tissues while retaining its spatial information. Here we provide detailed protocols to analyze lymphocyte, myeloid, and dendritic cell populations in tissue sections. Starting from cutting formalin-fixed paraffin-embedded sections, automatic multiplex staining procedures on an automated platform, scanning of the slides on a multispectral imaging microscope, to the analysis of images using an in-house-developed machine learning algorithm ImmuNet. These protocols can be applied to a variety of tumor specimens by simply switching tumor markers to analyze immune cells in different compartments of the sample (tumor versus invasive margin) and apply nearest-neighbor analysis. This analysis is not limited to tumor samples but can also be applied to other (non-)pathogenic tissues. Improvements to the equipment and workflow over the past few years have significantly shortened throughput times, which facilitates the future application of this procedure in the diagnostic setting.

Yi Qi Chu Tan Formula (YQCTF) inhibited the progress of lung cancer via regulating tumor-associated neutrophil: An integrated study of network pharmacology, proteomics and pharmacodynamics

Ethnopharmacological relevanceYi Qi Chu Tan Formula (YQCTF), a prescription consisting of eight traditional Chinese medicine for treating lung cancer, has been clinically proven to be effective in improving the life quality and prolonging the survival time of non-small cell lung cancer (NSCLC) patients. Aim of the studyThis study aimed to evaluate the therapeutic efficacy of YQCTF on NSCLC mice model and further explore its therapeutic targets by using network pharmacology, proteomics and pharmacodynamic methodologies. Materials and methodsThe network pharmacology analysis was firstly conducted to screen out the potential active ingredients and therapeutic targets of YQCTF against NSCLC. Three kinds of extracts, i.e. the water extract (WE), water extraction-alcohol precipitation (WEAP) and alcohol extract (AE) of YQCTF were prepared, which chemical compositions were subsequently analyzed by using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS), and which anti-neoplastic efficacy was examined on NSCLC mice model. Mice tumor tissues were collected for proteomics analysis, and the immunomodulatory effects of YQCTF extracts on the tumor microenvironment (TME) were further validated by using flow cytometry, immunofluorescence, ELISA and Western blot. ResultsNetwork pharmacology identified 60 conjunct genes and ample cancer-related signaling pathways as potential therapeutic targets of YQCTF. Protein-protein interaction (PPI), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that YQCTF might negatively regulate cancer-related inflammation. UPLC-MS/MS analysis showed that the main components of YQCTF include at least ginsenosides, solasodine, solamargine, solasonine, peimisine, peiminine, peimine and sipeimine-3β-D-glucosihde. All kinds of YQCTF extracts significantly inhibited the growth of lung cancer allograft and regulated the ratio of immune cells in tumor tissues, i.e. upregulated the fractions of T cells, promoted the maturation of dendritic cells (DCs), increased the M1/M2 ratio of tumor-related macrophages, but reduced the number of Tregs and immunosuppressive neutrophils. Proteomics identified neutrophils to be the most prominently enriched target linked to NETs formation in mice tumor tissue, which is verified by the downregulation of neutrophil recruiting factors involving IL-6, HIF-1α and IL-8, as well as the decreases of NETs-related biomarkers including H3cit, MPO, CD18, MMP9 and ICAM-1 in immunofluorescence, ELISA and Western blot analysis. ConclusionYQCTF inhibited the progress of mice NSCLC allograft, suppressed the pro-tumorigenic tumor-associated neutrophils and improved the tumor immune microenvironment (TIME).

Anti–PD-1 combination regimen as first-line therapy in advanced biliary tract cancer and biomarker exploration: A retrospective study.

e16130 Background: Combination strategy of immune checkpoint inhibitors has potential to replace chemotherapy as a new first-line therapy for advanced biliary tract cancer (BTC). The aims of this study were to assess the efficacy of anti-PD-1 combination therapy in the first-line treatment of advanced BTC and to find reliable biomarkers associated with overall survival (OS). Methods: Clinical data from patients with advanced BTC who received chemotherapy or anti-PD-1 combination therapy as first-line were collected. The primary outcome of this study was OS. Blood test results were collected from patients who received anti-PD-1 in the week prior to treatment to calculate inflammation scores and analyze their relationship with OS. A total of eight scores were selected for analysis, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein (CRP) ratio (LCR), lymphocyte-to-monocyte ratio (LMR), CRP to-albumin ratio (CAR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), and pan-immune-inflammation value (PIV). Moreover, archival tissues were collected for genetic testing and immunohistochemical staining to analyze genetic changes and the infiltration of immune cells in tumor tissues in relation to survival. Results: From January, 2018, to July, 2022, 64 patients were recruited: 11 were in the chemotherapy group, 21 were in the anti-PD-1 plus chemotherapy group, 21 were in the anti-PD-1 plus targeted therapy group and 11 were in the triple group (anti-PD-1 plus chemotherapy and targeted therapy). The median overall survival (mOS) was 7.9 months, 11.3 months, 12.8 months and 28.7 months, respectively. Compared to first-line chemotherapy, mOS was significantly prolonged in the triple group ( p= 0.031). The results of inflammation scores showed that patients with high LCR (≥0.4), high LMR (≥2.5), low CAR ( < 0.18), high PNI (≥44.3) or low PIV ( < 480.9) had significantly prolonged mOS compared to those with different scores ( p< 0.05). Genetic testing results suggested that patients with poor survival all had TP53 mutations and had higher levels of KRAS and ERBB2 mutations. Immunohistochemical results showed that a low FOXP3/CD8 ratio (≤0.27) was associated with prolonged OS ( p= 0.029). With CD4-low, CD8-high, CD56-positive, CD163-high, FOXP3-high and MPO-high in TME as one factor, we calculated immunoscore according to the number of factors. The high immunoscore group ( > 2) showed significantly superior OS ( p= 0.003). Conclusions: First-line anti-PD-1 antibody combination therapy was superior to chemotherapy, and triple therapy significantly improved survival. Peripheral blood immune-inflammation score, FOXP3/CD8 ratio and immunoscore have potential as biomarkers for predicting the efficacy of first-line anti-PD-1 antibody therapy in advanced BTC.

Evaluation of GREM1 and THBS2 as prognostic markers in in non-small cell lung cancer.

To analyze the correlation between bone morphogenetic protein (BMP) antagonist Gremlin 1 (GREM1), Thrombospondin-2 (THBS2) and immune cell infiltration in non-small cell lung cancer (NSCLC) and the related clinical significance. A total of 150 NSCLC patients admitted to our hospital during May 2019-January 2022 were picked. The expression of GREM1 and THBS2 and the infiltration of immune cells in tumor tissues were detected through immunohistochemistry (IHC). These objects were graded as GREM1-positive group (n = 97), GREM1-negative group (n = 53), THBS2-positive group (n = 102) and THBS2-negative group (n = 48) according to the expression of GREM1 and THBS2. The correlation between the expression of GREM1 and THBS2 with immune cell infiltration and clinicopathological indicators was analyzed. Kaplan-Meier survival analysis was adopted to analyze the relationship between the expression of GREM1 and THBS2 and the prognosis in NSCLC tissues. The overall progression-free survival (PFS) of the two groups were compared by log-rank test. The results of IHC showed that the positive expression rate of GREM1 was 64.67% (97/150) in cancer tissues and 36.00% (54/150) in adjacent tissues. The positive expression rate of THBS2 was 68.00% (102/150) in cancer tissues and 25.33% (38/150) in adjacent tissues. The positive expression rate of GREM1 and THBS2 in cancer tissues was both much higher than that in adjacent tissues (P < 0.01). GREM1-positive group had much higher proportion of tumor diameter ≥ 2cm, stage III-IV and lymph-node metastasis than GREM1-negative group (P < 0.05). THBS2-positive group had markedly higher proportion of tumor diameter ≥ 2cm, stage III-IV, lymph-node metastasis and high differentiation than THBS2-negative group (P < 0.01). GREM1-positive group had much higher level of CD3 + T, and sharply lower level of CD8 + T and CD11c + DCs than GREM1-negative group (P < 0.01). THBS2-positive group had much higher level of CD3 + T, and sharply lower level of CD8 + T and CD11c + DCs than THBS2-negative group (P < 0.01). According to Kaplan-Meier survival analysis, the overall median progression-free survival (PFS) was 7.45months. Log-rank test showed that NSCLC patients with positive GREM1 and THBS2 had much shorter PFS than negative patients (P < 0.01). Log-rank test showed that the expression of GREM1 and THBS2 was related to the PFS of patients (P < 0.01). GREM1 and THBS2 were highly expressed in NSCLC tissues and acted as pro-oncogenes in the development and progression of NSCLC, which aggravated the disease by mediating immune cell infiltration.

Abstract 2200: Transcriptomic profiling identifies an amino acid metabolism-related prognostic gene signature in lung adenocarcinoma patients

Abstract Lung cancer is by far the most common cancer-related fatality. In addition to the existing standard treatment methods, it is urgent to develop new therapy methods to improve the survival rate of patients. Amino acid metabolism plays a crucial role in tumor development. Cancer cells rely on amino acids for replication, energy source, redox homeostasis, and release metabolites that recruit and stimulate immunosuppressive cells. This study constructed a novel prognostic signature model of lung adenocarcinoma (LUAD) composed of amino acid metabolism-related genes and assessed immune cell infiltration characteristics and predictive value for patient therapy. We screened differentially expressed genes involved in amino acid metabolic pathways in LUAD tumor tissues versus normal tissues from RNA-seq data of The Cancer Genome Atlas. Then we performed a multivariate cox analysis of 9 genes significantly associated with patients’ overall survival, which established a new prognostic signature. Dividing the patients into high- and low-risk groups using a cutoff value of -0.36, the outcome showed that the risk score of this model could predict survival of LUAD patients with relatively high accuracy (ROC-AUC (max)=0.73). Subsequently, we utilized the ssGSEA method to quantify the infiltration of immune cells. We found that several immune cell subpopulations were significantly altered abundance between the high- and low-risk patients. Immune cell subpopulations, such as mast cell, plasmacytoid dendritic cell, and central memory CD4 T cell, were significantly abundant in the low-risk patients. After ESTIMATE algorithm evaluation, a method for estimating the proportion of stromal and immune cells in tumor tissues based on gene expression profiles, we observed that immune and stroma scores were markedly upregulated in low-risk patients, suggesting that the immune and stromal activity were increased. The key molecules of this signature exhibited a significant correlation with the expression of immune checkpoint molecules. Moreover, multivariate cox regression model analysis was performed with patients’ age, gender, clinical stage, T stage, M stage, N stage and risk score. The results indicated that the risk score signature was a significant and independent prognostic biomarker for the prognostic prevision of LUAD patients.Finally, the risk score based on the amino acid metabolism-related signature was successfully validated by the data of LUAD patients in the GEO dataset GES30219.These findings suggest that the prognostic signature based on the expression of genes involved in amino acid metabolism may be useful and effective. We further characterized one of the 9 genes involved in tryptophan metabolism for its biological implications in tumor progression and construction of immuno-suppressive tumor microenvironment by experimental procedures with human LUAD cell lines. Citation Format: Huihui Xiang, Rika Kasajima, Hiroyuki Ito, Tomoyuki Yokose, Takashi Oshima, Tetsuro Sasada, Yohei Miyagi. Transcriptomic profiling identifies an amino acid metabolism-related prognostic gene signature in lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2200.

Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment.

Programmed cell death protein 1 (PD-1) receptor has two ligands,programmed death-ligand 1 (PD-L1) and PD-L2. When compared with PD-L1, PD-L2 has not received much attention, and its role remains unclear. The expression profiles of pdcd1lg2 (PD-L2-encoding gene) mRNA and PD-L2 protein were analyzed using TCGA, ICGC, and HPA databases. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of PD-L2. We used GSEA, Spearman's correlation analysis and PPI network to explore the biological functions of PD-L2. PD-L2-associated immune cell infiltration was evaluated using the ESTIMATE algorithm and TIMER 2.0. The expressions of PD-L2 in tumor-associated macrophages (TAMs) in human colon cancer samples, and in mice in an immunocompetent syngeneic setting were verified using scRNA-seq datasets, multiplex immunofluorescence staining, and flow cytometry. After fluorescence-activated cell sorting, flow cytometry and qRT-PCR and transwell and colony formation assays were used to evaluate the phenotype and functions of PD-L2+TAMs. Immune checkpoint inhibitors (ICIs) therapy prediction analysis was performed using TIDE and TISMO. Last, a series of targeted small-molecule drugs with promising therapeutic effects were predicted using the GSCA platform. PD-L2 was expressed in all the common human cancer types and deteriorated outcomes in multiple cancers. PPI network and Spearman's correlation analysis revealed that PD-L2 was closely associated with many immune molecules. Moreover, both GSEA results of KEGG pathways and GSEA results for Reactome analysis indicated that PD-L2 expression played an important role in cancer immune response. Further analysis showed that PD-L2 expression was strongly associated with the infiltration of immune cells in tumor tissue in almost all cancer types, among which macrophages were the most positively associated with PD-L2 in colon cancer. According to the results mentioned above, we verified the expression of PD-L2 in TAMs in colon cancer and found that PD-L2+TAMs population was not static. Additionally, PD-L2+TAMs exhibited protumor M2 phenotype and increased the migration, invasion, and proliferative capacity of colon cancer cells. Furthermore, PD-L2 had a substantial predictive value for ICIs therapy cohorts. PD-L2 in the TME, especially expressed on TAMs, could be applied as a potential therapeutic target.

The CXCL10/CXCR3 Pathway Contributes to the Synergy of Thermal Ablation and PD-1 Blockade Therapy against Tumors

As a practical local therapeutic approach to destroy tumor tissue, thermal ablation can activate tumor-specific T cells via enhancing tumor antigen presentation to the immune system. In the present study, we investigated changes in infiltrating immune cells in tumor tissues from the non-radiofrequency ablation (RFA) side by analyzing single-cell RNA sequencing (scRNA-seq) data of tumor-bearing mice compared with control tumors. We showed that ablation treatment could increase the proportion of CD8+T cells and the interaction between macrophages and T cells was altered. Another thermal ablation treatment, microwave ablation (MWA), increased the enrichment of signaling pathways for chemotaxis and chemokine response and was associated with the chemokine CXCL10. In addition, the immune checkpoint PD-1 was especially up-regulated in the infiltrating T cells of tumors on the non-ablation side after thermal ablation treatment. Combination therapy of ablation and PD-1 blockade had a synergistic anti-tumor effect. Furthermore, we found that the CXCL10/CXCR3 axis contributed to the therapeutic efficacy of ablation combined with anti-PD-1 therapy, and activation of the CXCL10/CXCR3 signaling pathway might improve the synergistic effect of this combination treatment against solid tumors.

Comprehensive analysis of cuproptosis-related lncRNAs in immune infiltration and prognosis in hepatocellular carcinoma

BackgroundBeing among the most common malignancies worldwide, hepatocellular carcinoma (HCC) accounting for the third cause of cancer mortality. The regulation of cell death is the most crucial step in tumor progression and has become a crucial target for nearly all therapeutic options. Cuproptosis, a copper-induced cell death, was recently reported in Science. However, its primary function in carcinogenesis is still unclear.MethodsCuproptosis-related lncRNAs significantly associated with overall survival (OS) were screened by stepwise univariate Cox regression. The signature of cuproptosis-related lncRNAs for HCC prognosis was constructed by the LASSO algorithm and multivariate Cox regression. Further Kaplan–Meier analysis, proportional hazards model, and ROC analysis were performed. Functional annotation was performed using gene set enrichment analysis (GSEA). The relationship between prognostic cuproptosis-related lncRNAs and HCC prognosis was further explored by GEPIA(http://gepia.cancer-pku.cn/) online analysis tool. Finally, we used the ESTIMATE and XCELL algorithms to estimate stromal and immune cells in tumor tissue and cast each sample to infer the underlying mechanism of cuproptosis-related lncRNAs in the tumor immune microenvironment (TIME) of HCC patients.ResultsFour cuproptosis-related lncRNAs were used to construct a prognostic lncRNA signature, which was an independent factor in predicting OS in HCC patients. Kaplan–Meier curves showed significant differences in survival rates between risk subgroups (p = 0.002). At the same time, we found that the expression levels of most immune checkpoint genes increased with increasing risk scores. Tumorigenesis and immunological-related pathways were primarily enhanced in the high-risk group, as determined by GSEA. The results of drug sensitivity analysis showed that compared with patients in the high-risk group, the IC50 values of erlotinib and lapatinib were lower in patients in the low-risk group, while the opposite was true for sunitinib, paclitaxel, gemcitabine, and imatinib. We also found that elevated AL133243.2 expression was significantly associated with worse OS and disease-free survival (DFS), more advanced T stage and higher tumor grade, and reduced immune cell infiltration, suggesting that HCC patients with low AL133243.2 expression in tumor tissues may have a better response to immunotherapy.ConclusionCollectively, the cuproptosis-associated lncRNA signature can serve as an independent predictor to guide individual treatment strategies. Furthermore, AL133243.2 is a promising marker for predicting immunotherapy response in HCC patients. This data may facilitate further exploration of more effective immunotherapy strategies for HCC.

Comprehensive Metabolic Profiling and Genome-wide Analysis Reveal Therapeutic Modalities for Hepatocellular Carcinoma.

Understanding the details of metabolic reprogramming in hepatocellular carcinoma (HCC) is critical to improve stratification for therapy. Both multiomics analysis and cross-cohort validation were performed to investigate the metabolic dysregulation of 562 HCC patients from 4 cohorts. On the basis of the identified dynamic network biomarkers, 227 substantial metabolic genes were identified and a total of 343 HCC patients were classified into 4 heterogeneous metabolic clusters with distinct metabolic characteristics: cluster 1, the pyruvate subtype, associated with upregulated pyruvate metabolism; cluster 2, the amino acid subtype, with dysregulated amino acid metabolism as the reference; cluster 3, the mixed subtype, in which lipid metabolism, amino acid metabolism, and glycan metabolism are dysregulated; and cluster 4, the glycolytic subtype, associated with the dysregulated carbohydrate metabolism. These 4 clusters showed distinct prognoses, clinical characteristics and immune cell infiltrations, which was further validated by genomic alterations, transcriptomics, metabolomics, and immune cell profiles in the other 3 independent cohorts. Besides, the sensitivity of different clusters to metabolic inhibitors varied depending on their metabolic features. Importantly, cluster 2 is rich in immune cells in tumor tissues, especially programmed cell death protein 1 (PD-1)-expressing cells, which may be due to the tryptophan metabolism disorders, and potentially benefiting more from PD-1 treatment. In conclusion, our results suggest the metabolic heterogeneity of HCC and make it possible to treat HCC patients precisely and effectively on specific metabolic characteristics.

Single-cell transcriptomic analysis of the role of HPV16-positive macrophages in cervical cancer prognosis.

Almost all cases of cervical cancer (CC) can be attributed to high-risk HPVs infections in keratinocytes. However, it is unknown whether HPV invades immune cells such as macrophages and T cells. We analyzed the single-cell transcriptome of the CC and its adjacent tissues and found that HPV16 genes, including E1, E6, and E7, expressed in the macrophages and CD8+ T cells in addition to the malignant cells. HPV16+ macrophages highly expressed the genes that promote cell adhesion and the favorable genes such as WAS, IQCB1, MYO1F, and PDZD11 in CC prognosis. The transcription factor KLF5 potentially accounted for the induction of these protective genes and thus facilitated the infiltration of the immune cells in tumor tissues. Our single-cell transcriptome analysis suggests the potential value of the HPV16+ macrophage in CC prognosis. However, extensive experimental studies investigating the characteristics and functions of the HPV+ immune cells are still required. This article is protected by copyright. All rights reserved.

Highlights from Recent Cancer Literature

Breaking Insights| July 05 2022 Highlights from Recent Cancer Literature Author & Article Information Online Issn: 1538-7445 Print Issn: 0008-5472 ©2022 American Association for Cancer Research2022American Association for Cancer Research Cancer Res (2022) 82 (13): 2327–2328. https://doi.org/10.1158/0008-5472.CAN-82-13-BI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record July 5 2022 Citation Highlights from Recent Cancer Literature. Cancer Res 1 July 2022; 82 (13): 2327–2328. https://doi.org/10.1158/0008-5472.CAN-82-13-BI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search A current limitation of the effectiveness of immunotherapies has toxic effects on the immune system in noncancerous tissues. To identify immune pathways unique to tumors, Mair and colleagues compared immune phenotypes in human head and neck squamous cell carcinomas (HNSCC) with inflamed surrounding oral mucosal tissue and with peripheral blood immune cells, using flow cytometry, single cell transcriptomics, and the NicheNet ligand-receptor analysis tool for cell-cell interactions. First, they found tremendous congruence between immune cells in tumor tissues compared with cells in inflamed nontumor tissues. Second, they discovered that IL1R1 and the previously defined marker ICOS were almost exclusively induced on tumor-infiltrating regulatory T cells (Treg). Third, they found that IL1R1+ Tregs were highly suppressive. IL1R1 was induced on Tregs acutely, therefore its expression in tumors was likely a consequence of the high activation state of Tregs in tumors. Further, Tregs expressed high levels of the chemokine receptor CXCR6.... You do not currently have access to this content.

ACYP1 Is a Pancancer Prognostic Indicator and Affects the Immune Microenvironment in LIHC.

BackgroundACYP1 plays important physiological and metabolic roles in glycolysis and membrane ion pump activity by catalyzing acyl phosphate hydrolysis. ACYP1 is related to tumorigenesis and progression and poor prognosis in gastrointestinal cancer. However, its pancancer roles and mechanisms are unclear. Our study aimed to understand the ACYP1 expression signature and prognostic value across cancers and investigate immune infiltration patterns in liver hepatocellular carcinoma (LIHC) and verify them in LIHC samples.MethodsTranscriptional expression profiles of ACYP1 across cancers were analyzed using Oncomine and TIMER. The prognostic value of ACYP1 was assessed across PrognoScan, Kaplan—Meier Plotter, and GEPIA. Significant pathways associated with ACYP1 in LIHC were obtained via Gene Set Enrichment Analysis. The correlation between ACYP1 expression and immune infiltration in LIHC was investigated using TIMER. We validated ACYP1 expression, prognostic value, and association with immune cells in tumor tissues by immunohistochemistry and flow cytometry.ResultsACYP1 was overexpressed across cancers. High expression of ACYP1 correlated with a poor prognosis in most tumor types, especially in LIHC. ACYP1 was significantly implicated in immune and metabolic related pathways. High ACYP1 expression showed significant correlations with the abundances of Th2 cells, Tregs, macrophages, dendritic cells, and myeloid-derived suppressor cells in LIHC. LIHC patients with high ACYP1 expression showed significantly shorter overall survival and relapse-free survival rates concomitant with increased infiltration of CD4+ T cells. Mouse subcutaneous tumors with ACYP1 overexpression exhibited significantly accelerated tumor progression with increased aggregation of CD4+ T cells.ConclusionOverall, ACYP1 may serve as a vital prognostic biomarker and play an immunoregulatory role in LIHC.

Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice.

Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.

Neoantigens and the tumor microenvironment play important roles in the prognosis of high-grade serous ovarian cancer

BackgroundDespite the consistency of patient age, disease stage and treatment options, the prognosis of different high-grade serous ovarian carcinoma (HGSOC) patients is different. Here, we sought to measure predictive biomarkers for distinct responses to platinum-based chemotherapy and immunotherapy benefits.MethodsSixteen HGSOC patients receiving debulking surgery and adjuvant first-line combination chemotherapy at Peking Union Medical College Hospital (PUMCH) were enrolled. Whole exome sequencing (WES) and RNA-seq were performed on tumor and normal tissues of these patients.ResultsThe tumor mutational burden (TMB) and intratumoral heterogeneity (ITH) of the platinum-resistant group were significantly higher than those of the platinum-sensitive group (P=0.0321 and P=0.0452, respectively). TMB, neoantigen and ITH had certain predictive value according to the area under the receiver operating characteristic (ROC) curve (AUC 0.7778 for TMB, 0.7619 for neoantigen, 0.7778 for ITH). The infiltration of other immune cells in tumor tissues was different between the two groups, but the difference was not significant. Univariate Cox proportional hazard analysis revealed poorer progression-free survival (PFS) for those patients who carried a higher number of neoantigens (P =0.0069), higher TMB (P =0.0083), and higher ITH (P =0.0249). Further Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis indicated the Differentially expressed genes (DEGs) in platinum-resistant and platinum-sensitive patients were mainly enriched in the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) signaling pathway and focal adhesion pathway, which are associated with platinum resistance.ConclusionsHigher TMB, neoantigen and ITH may account for the worse prognosis of patients with platinum-based chemotherapy and higher TMB was observed in the platinum-resistant group, which could make the patients in the platinum-resistant group to be the better candidates for immunotherapy.

The correlation between infiltration of FoxP3+ Tregs, CD66b+ TANs and CD163+ TAMs in colorectal cancer.

IntroductionThe infiltration of immune cells in tumor tissue is affected by the tumor microenvironment. However, the relationship between the infiltration of regulatory T cells (Tregs), tumor-associated neutrophils (TANs) and tumor-associated macrophages (TAMs) in colorectal cancer (CRC) remains unclear.Material and methodsTissue microarray and immunohistochemistry were used to detect the infiltration of FoxP3+ Tregs, CD66b+ TANs and CD163+ TAMs in 249 CRC samples (training cohort) and 243 CRC samples (validation cohort). The relationship between two cells was evaluated by Spearman’s rank correlation coefficient and comparison between two groups was analyzed by Mann-Whitney U test.ResultsThe continuous variable positive cell numbers were non-normally distributed. Spearman correlation analysis showed that CD66b+ TAN level in cancer tissues was negatively related to FoxP3+ Treg level (correlation coefficient: –0.495, p < 0.05) and CD163+ TAM level (correlation coefficient: –0.266, p < 0.05), and FoxP3+ Treg level was positively related to CD163+ TAM level (correlation coefficient: 0.467, p < 0.05) in the training cohort. The numbers of FoxP3+ Tregs were significantly different between low and high CD66b+ TAN level groups (p < 0.001), as well as that of CD66b+ TANs in low and high CD163+ TAM level groups and CD163+ TAMs in different FoxP3+ Treg level groups. The results of the validation cohort were similar to those of the training cohort.ConclusionsThere is a negative correlation between infiltration of CD66b+ TANs and that of FoxP3+ Tregs or CD163+ TAMs, and a positive correlation between infiltration of FoxP3+ Tregs and CD163+ TAMs in CRC tissues.