Cancer Immunology, Immunotherapy最新文献

Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 blockade, have shown great success in treating melanoma. PD-L1 (B7-H1, CD274), a ligand of PD-1, binds to PD-1 on T cells, inhibiting their activation and proliferation through multiple pathways, thus dampening tumor-reactive T cell activity. Studies have linked PD-L1 expression in melanoma with tumor growth, invasion, and metastasis, making the PD-1/PD-L1 pathway a critical target in melanoma therapy. However, immune-related adverse events are common, reducing the effectiveness of anti-PD-L1 treatments. Recent evidence suggests that the gut microbiome significantly influences anti-tumor immunity, with the microbiome potentially reprogramming the tumor microenvironment and overcoming resistance to anti-PD-1 therapies in melanoma patients. This review explores the mechanisms of PD-1/PD-L1 in melanoma and examines how gut microbiota and its metabolites may help address resistance to anti-PD-1 therapy, offering new insights for improving melanoma treatment strategies.

T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a recently-identified immune checkpoint molecule, and no study ever explores the prognostic significance of TIGIT on bone marrow T cells of newly-diagnosed acute myeloid leukemia (AML) patients. We collected fresh marrow samples from 71 adult AML patients at diagnosis and 31 healthy donors (HDs) to test for TIGIT and PD1 expression in T cells by flow cytometry. Fifteen newly-diagnosed AML patients and six HDs were performed T cell activation in vitro and tested intracellular TNF-α and INF-γ production. Three bone marrow samples of AML patients were performed single cell RNA-sequencing (scRNA-seq). AML patients had significantly higher frequency of TIGIT + cells in CD4 + T cells but similar frequency in CD8 + T cells compared with HDs (p = 0.0006 and 0.77). High percentage of TIGIT + PD1 + in CD8 + T cells independently predicted poor relapse-free survival (RFS) (p = 0.029). Differing from HDs, AML patients had lower level of intracellular TNF-α and INF-γ in TIGIT + cells compared with their TIGIT- counterparts in both CD4 + T and CD8 + T cells. TIGIT + PD1 + CD8 + T cells of patients exhibited significantly lower level of intracellular TNF-α compared with those of HDs (p = 0.024). scRNA-seq data showed that TIGIT + PDCD1 + CD8 + T cells had significantly higher exhaustion score than TIGIT + and PD1 + CD8 + T cells and lower cytotoxic score than TIGIT + CD8 + T cells (p = 0.0016, 0.012 and 0.0014). Therefore, CD8 + T cells with TIGIT and PD1 co-expression exhibited high degree of exhaustion and dysfunctional cytotoxicity, and high percentage of bone marrow TIGIT + PD1 + in CD8 + T cells at diagnosis predicted poor outcome in AML.

Objective: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with a need for improved treatment strategies. Antigen-presenting cells (APCs) have emerged as important modulators of immune responses in the tumor microenvironment (TME). This study aimed to explore the role of these cells in CRC and their potential synergy with radiation therapy (RT).

Methods: Single-cell sequencing was performed before and after neoadjuvant therapy (NAT) to identify changes in myeloid cells within the tumor microenvironment, which was compared with peripheral blood of the same patients. The effect of RT with/without immunotherapy on these cells was evaluated in vivo and in vitro.

Results: Single-cell sequencing showed that SIRPα + CD209 + cells are specialized antigen-presenting cells which are found to decrease in the TME while increasing in the peripheral blood after NAT. In vitro study confirmed their resistance to RT with further upregulated SIRPα expression and enhanced antigen presentation capability induced by RT. Moreover, these cells are involved in the superior tumor control by combination of RT and anti-SIRPα treatment.

Conclusion: SIRPα + CD209 + APCs play a pivotal role in CRC immune modulation and show potential for synergy with RT. These cells could be a biomarker for antigen-presenting capacity, and enhancing their APC function could potentially improve RT/PD1 effectiveness by combination with anti-SIRPα in CRC.

ISG15, an interferon-stimulated ubiquitin-like protein, plays a multifaceted role in tumorigenesis and immune regulation. This study comprehensively evaluates ISG15 as a prognostic biomarker and predictor of immunotherapy response through pan-cancer bioinformatics analysis and experimental validation. By integrating multiomics data from TCGA, GEO, and clinical cohorts, we found that ISG15 is significantly overexpressed in multiple cancers and generally correlates with poor prognosis. Elevated ISG15 expression is associated with increased immune checkpoint gene expression, particularly PD-L1, and immune infiltration, notably M2-like tumor-associated macrophages. Immunohistochemistry and multiplexed immunofluorescence confirmed a strong positive correlation between ISG15, PD-L1, and M2-TAM infiltration in lung and gastric cancer samples. Functional analysis at the single-cell level revealed significant associations between ISG15 and tumor proliferation, angiogenesis, and immune suppression. Immunotherapy cohort analysis demonstrated that tumors with high ISG15 expression responded favorably to PD-L1 inhibitors but exhibited resistance to CTLA-4 blockade, findings further validated in lung cancer patients receiving anti-PD-1 therapy. These results suggest that ISG15 is a promising biomarker for prognosis and immunotherapy response prediction across cancers. Its integration into clinical decision-making may enhance personalized treatment strategies, improve immunotherapy outcomes, and provide new insights into the tumor immune microenvironment, cancer progression, and potential therapeutic targets for future drug development.

CXCR5 is a chemokine receptor that promotes B cell follicular formation and antibody production. Indeed, CXCR5 has been found to be expressed in a variety of cancers; however, the role of CXCR5 expression in clear-cell renal cell carcinoma (ccRCC) remains unclear. We aimed to determine the impact of cellular CXCR5 expression on cancer outcomes, the PD-1/PD-L1 axis, and genetic states in patients with ccRCC. First, multiplex immunofluorescence staining for CXCR5, CD4, CD8, and AE1/AE3, along with automated single-cell counting, was performed to assess cellular CXCR5 expression in ccRCC and its association with prognosis. Second, the tumour microenvironment (TME) was analysed, with a focus on the relationship between the PD-1/PD-L1 axis and CXCR5 expression. Finally, an integrated analysis of CXCR5 expression and genomic mutation information was conducted to reveal the genetic background underlying CXCR5 expression. A total of 105 ccRCC patients were included. Among the 696,964 cells analysed, the distribution of CXCR5-expressing cells was as follows: 30% CXCR5⁺CD4⁺ cells, 9% CXCR5⁺CD8⁺ cells, and 26% CXCR5⁺AE1/AE3⁺ cells. Survival analysis revealed that tumours with low-CXCR5⁺CD8⁺ cells had a poor prognosis; TME analysis revealed a relationship between low-CXCR5⁺CD8⁺ status and a highly suppressive PD-L1-positive immune environment. Genomic analysis revealed a correlation between low-CXCR5⁺CD8⁺ status and high rates of alterations in chromatin remodelling genes, including PBRM1. This study highlights the significance of CXCR5⁺CD8⁺ cells in ccRCC, demonstrating their clinical implications and revealing the immunogenomic landscape underlying CXCR5 expression.

Introduction: Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor survival outcomes. The CD70-CD27 axis has been implicated in immune regulation and tumor progression across cancers, but its role in SCLC has not yet been elucidated. This research explores the expression patterns and prognostic significance of CD70 and CD27 in early-stage SCLC.

Methods: In this retrospective study, we analyzed 190 surgically resected SCLC tumor samples using immunohistochemistry (IHC) for CD70 and CD27 expression and RNAscope for CD70 RNA detection. Immune infiltration was assessed using CD45, CD8, and CD20 staining. Quantification of RNAscope signals was performed using QPath software. Kaplan-Meier survival analysis and multivariate Cox regression were used to assess the prognostic impact of CD70, CD27, and immune cell infiltrates on overall survival (OS).

Results: CD70 was expressed in 46% of tumors, primarily within tumor nests, with lower expression in stromal areas. High CD70 expression correlated with significantly decreased OS (p = 0.0078, HR: 1.795) without any correlation with CD45 + , CD8 + or CD20 + immune cell infiltrates. CD27 expression was mainly confined to the stroma, and it did not show a significant association with OS (p = 0.582). Importantly, high CD27 expression was linked to reduced CD45 + and CD8 + cell densities in the stroma. Both CD70 and CD27 were expressed on CD68 + macrophages, CD27 was expressed on CAFs, and both molecules exhibited a partial coexpression with CD3. Furthermore, patients with high CD20 + B-cell densities or the presence of tertiary lymphoid structures (TLS) had significantly improved OS (p = 0.0017, HR: 0.491), suggesting the importance of B-cell-related immune responses in SCLC prognosis.

Conclusion: CD70, B-cell density and the presence of TLSs, but not CD27, emerged as a significant prognostic biomarker for OS in surgically treated SCLC, suggesting its potential as a therapeutic target.

Background: This study aimed to identify clinical factors and develop a predictive model for pathological complete response (pCR) and major pathological response (MPR) in non-small cell lung cancer (NSCLC) patients receiving neoadjuvant chemotherapy combined with immune checkpoint inhibitors (ICIs).

Methods: Cases meeting inclusion criteria were divided into high- and low-risk groups according to 75 clinical indicators based on tenfold LASSO selection. Logistic regression was employed to analyze both pCR and MPR. The accuracy of the nomograms was assessed using the time-dependent area under the curve (AUC).

Results: A total of 297 patients from four multiple centers were included in the study, with 212 assigned to the training set and 85 to the testing set. The AUC was determined for the prediction of pCR (training: 0.97; testing: 0.88) and MPR (training: 0.98; testing: 0.81). Significant associations were observed between the preoperative tumor maximum diameter, preoperative tumor maximum standardized uptake value (SUV_max), changes in tumor SUV_max, percentage of tumor reduction, baseline total prostate-specific antigen (TPSA) and pathological response (P < 0.001).

Conclusions: The combined application of clinical indicators including non-invasive tumor imaging and hematology can help clinicians to obtain a higher ability to predict NSCLC patient's pathological remission, and the effect is better than that of clinical factors alone. These findings could help guide personalized treatment strategies in this patient population.

Cancer immunotherapy has transformed the treatment landscape, introducing new strategies to fight various types of cancer. This review examines the important role of vaccines in cancer therapy, focusing on recent advancements such as dendritic cell vaccines, mRNA vaccines, and viral vector-based approaches. The relationship between cancer and the immune system highlights the importance of vaccines as therapeutic tools. The discussion covers tumor cell and dendritic cell vaccines, protein/peptide vaccines, and nucleic acid vaccines (including DNA, RNA, or viral vector-based), with a focus on their effectiveness and underlying mechanisms. Combination therapies that pair vaccines with immune checkpoint inhibitors, TIL therapy, and TCR/CAR-T cell therapy show promising potential, boosting antitumor responses. Additionally, the review explores the regulatory functions of microRNAs (miRNAs) in cancer development and suppression, featuring miR-21, miR-155, the let-7 family, and the miR-200 family, among others. These miRNAs influence various pathways, such as PI3K/AKT, NF-κB, and EMT regulation, providing insights into biomarker-driven therapeutic strategies. Overall, this work offers a thorough overview of vaccines in oncology and the integrative role of miRNAs, setting the stage for the next generation of cancer immunotherapies.

RING finger protein 2 (RNF2) has been shown to promote tumor growth in various cancer types. However, the immune regulatory function of RNF2 in the tumor microenvironment is unclear. Here, we report that upregulation of RNF2 is positively correlated with the tumor burden and poor prognosis in hepatocellular carcinoma patients and fosters an immunosuppressive microenvironment with increased MDSCs recruitment, and reduced T cell activation. Mechanistically, RNF2 binds with TRAF2 and directly mediates K63-linked TRAF2 ubiquitination. This modification of TRAF2 enables NF-κB hyperactivation in tumor cells, which subsequently induces CXCL1 transcription to enhance MDSCs migration. Furthermore, RNF2 knockout improves responsiveness to anti-PD-1 therapy in immunocompetent mice, as evidenced by enhancing infiltration of CD8⁺T cells into the tumor and a reduction in MDSC levels. Collectively, our experiments support that perturbing RNF2 and targeting MDSCs may afford therapeutic opportunities for hepatocellular carcinoma interception and prevention.