Cancer Immunology, Immunotherapy最新文献

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.

Regulatory T cells (Tregs) play an immunosuppressive role in tumor microenvironment (TME) in various of cancer types. However, how different Treg subsets influence and effect on head and neck squamous cell carcinoma (HNSCC) remain unclear. Here, using single-cell RNA sequencing (scRNA-seq), we identified an IL1R2+Treg subset which promoted the progression of HNSCC. Via tissue microassay (TMA) and enzyme-linked immunosorbent assay (ELISA), we verified the clinical diagnostic value of the IL1R2+Treg and soluble IL1R2 (sIL1R2). In addition, we constructed tumor-bearing mouse models to explore the antitumor effects of combined targeting IL1R2 and CTLA4. For mechanism, we found IL-1β promoted the expression of IL1R2 and CTLA4 in Tregs, and upregulated CTLA4 though NR4A1 translocation. These results revealed that IL1R2+Treg and serum IL1R2 level had potential diagnostic and prognostic value of HNSCC and combined targeting of IL1R2 and CTLA4 might be an effective strategy to inhibit tumor progression.

Given that natural killer (NK; CD3 - CD56 +) cells-mediated antibody-dependent cell cytotoxicity (ADCC) plays an important role in targeting neuroblastoma (NB) cells, adoptive cell therapy (ACT) utilizing expanded and activated haploidentical NK cells has emerged as a promising immunotherapeutic approach in pediatric patients with high-risk NB. In this pilot study, five pediatric patients with high-risk NB were enrolled. After harvesting hematopoietic progenitor cells (HPCs), patients received an intravenous infusion of high-activity iodine-131 (¹³¹I)-meta-iodobenzylguanidine (¹³¹I-MIBG). Seven days after the ¹³¹I-MIBG infusion and before the delivery of a single infusion of haploidentical purified NK cells, patients were administered a preparative regimen to establish a lymphodepleted host environment conducive to improved donor NK cell survival. Four days after the NK cell infusion, patients underwent the conditioning regimen, then received autologous hematopoietic stem cell transplantation (AHSCT). All patients achieved successful neutrophil and platelet engraftment. No adverse reactions were noted during or after the infusion of NK cells. Our study shows that incorporating NK cell infusion before AHSCT as a component of the conditioning regimen for consolidative therapy in pediatric patients with high-risk NB can be safe and well tolerated. IRCT Registration Number: IRCT20140818018842N32.

Microwave ablation (MWA) is a super minimally invasive therapeutic approach that has been widely applied in the treatment of non-small cell lung cancer (NSCLC). Although MWA can elicit antitumor immune responses, these immune responses are not relatively steady and insufficient to completely clear recurrence tumor cells within the body. Immunotherapy monotherapy has shown low clinical efficacy in the treatment of advanced NSCLC. MWA combined with immune checkpoint inhibitors (ICIs) is a promising therapeutic approach. However, the mechanism of synergic effect remains elusive. In this study, we have conducted a retrospective analysis of the clinical outcomes of MWA combined with ICIs, finding that the combinational therapy yielded superior Objective Response Rate and longer Progression-Free Survival. In preclinical models, we established a tumor rechallenged model to address post-MWA recurrence and to delve into the underlying mechanisms of the combined therapy. We observed that the combined treatment (MWA + PD-L1 blockade therapy) effectively addressed the issue of tumor recurrence in tumor rechallenged model. The combinational therapy increased the function and percentage of CD8⁺ tumor-infiltrating lymphocytes, enhanced the functionality of CD8⁺ T cells within tumor-draining lymph nodes (TdLNs), and elevated the proportion of T central memory cells. Additionally, the combined treatments promoted the proportion of Migration Dendritic Cells type 1 (Mig DC1) within TdLNs, thereby enhancing their activation potential. Notably, FTY720-mediated blockade of lymphocyte egress abolished the therapeutic benefits, confirming TdLNs-dependent systemic immunity. Moreover, the efficacy of the combinational therapy depended on the migration of T cells from TdLNs to tumor site. In summary, we proposed a potentially effective combined treatment regimen and have elucidated the underlying cellular mechanisms that underpin its efficacy.

Background: Malignant mesothelioma is a highly aggressive cancer with a poor prognosis and limited therapeutic options. The tumor microenvironment (TME) plays a pivotal role in driving tumor progression, with immune cells influencing disease outcomes. However, the molecular mechanisms underpinning mesothelioma's progression remain insufficiently understood. HLA-C, a class I major histocompatibility complex (MHC) molecule, has been implicated in immune modulation and cancer progression, but its specific role in mesothelioma has yet to be thoroughly investigated.

Methods: This study employed a comprehensive multi-omics approach, integrating single-cell RNA sequencing, expression quantitative trait loci (eQTL) analysis, and Mendelian randomization (MR), to elucidate the role of HLA-C in mesothelioma progression. We first analyzed HLA-C expression within the TME, with particular focus on immune cells, especially macrophages. Survival analysis was conducted using data from the TCGA mesothelioma cohort to assess the clinical relevance of HLA-C expression. We utilized mediated MR analysis to investigate the impact of DNA methylation on HLA-C expression, identifying key mediators such as inflammatory cytokines, immune cell populations, blood cell types, and metabolites that could potentially influence patient prognosis.

Results: HLA-C was predominantly expressed in macrophages, T cells, and NK cells within the TME, and higher expression levels were associated with improved patient survival. MR analysis revealed that DNA methylation regulates HLA-C expression, which in turn impacts mesothelioma outcomes. Mediated MR analysis, encompassing 91 inflammatory cytokines, 731 immune cell populations, 91 blood cell types, and 1400 metabolites, highlighted several critical mediators of HLA-C's effect on prognosis, including IL-10, CD33 expression on CD33dim HLA DR- myeloid cells, the reticulocyte perturbation response, and the ADP-to-citrate ratio. Gene set enrichment analysis (GSEA) showed significant enrichment of immune-related and inflammatory pathways in patients with high HLA-C expression.

Conclusion: HLA-C, regulated by DNA methylation, plays a central role in mesothelioma prognosis by modulating immune responses, inflammatory cytokines, blood cell populations, and metabolic processes within the TME. Our findings suggest that HLA-C could serve as both a prognostic biomarker and a potential therapeutic target for mesothelioma, offering new insights into the molecular mechanisms driving this aggressive cancer.

Immunoscore (IS), based on CD3/CD8, has been proposed to characterize the immune landscape of the tumor immune microenvironment and has demonstrated an association with the prognosis of laryngeal squamous cell carcinoma (LSCC). However, traditional IS does not include immunosuppressive cells. The purpose of this study is to evaluate the prognostic performance of cytotoxic-T-lymphocytes to immunosuppressive cells ratio (CIL) in laryngeal squamous cell carcinoma (LSCC) patients. Two cohorts were included in this study: The training cohort (N = 75) consisted of tumor tissue microarrays from LSCC patients in our department, and the validation cohort (N = 116) utilized bulk RNA-seq data from the TCGA database. Patients with high IS or CIL showed significantly prolonged overall survival and disease-free survival in both cohorts. Upon analyzing the relative contribution of each parameter, it was found that CIL exhibited the highest significance among the factors examined. It emerged as the strongest predictor of overall survival, emphasizing its crucial influence in determining the outcomes. The prognostic ability of IS-TCGA was similar to the original IS. Additionally, high CILM2-TCGA was associated with prolonged survival of patients with LSCC in the TCGA dataset. CIL, which is easier to construct than IS, proves to be reliable in predicting survival outcomes for patients with LSCC.

Chimeric antigen receptor (CAR) T-cell infusion (CTI) therapy has emerged as a breakthrough therapy in relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL), but a substantial number of patients still suffer treatment failure. Data on disease history, subsequent salvage therapies, and outcomes of patients who face treatment failure after the first CTI (CTI1) have not been reported in detail or systematically studied. Here, a retrospective analysis was performed on a total of 61 R/R B-NHL patients in whom salvage therapies were adopted after CTI1 treatment failure, with their clinical characteristics, subsequent management and outcomes described in detail. The results suggested that second-time CTI (CTI2) used as salvage therapy after failure of CTI1 could achieve a better transient overall response rate (ORR) than other salvage treatments (non-CTI2) in only a minority of patients (8/27 vs. 2/34, P=0.014). Nevertheless, the non-CTI2 group showed better event-free survival (EFS) (P = 0.007) and overall survival (OS) (P = 0.048) than the CTI2 group, with a median follow-up of 6.7 months vs. 4.7 months. In addition, univariate and multivariate analyses showed that only the status of the tumor at disease onset was an independent risk factor for survival; salvage therapy after CTI1 treatment failure was not. The adverse effects of CTI2 treatment were generally similar to those of non-CTI2 treatment, but the infection-related mortality was considerably higher. In conclusion, the prognosis of patients who fail CTI1 therapy is very poor regardless of the subsequent salvage therapies, and clinicians should be cautious about adopting CTI2 treatment after failure of treatment with the CD19/22 cocktail CTI1 in R/R B-NHL. Large-scale prospective studies are warranted, and new strategies are urgently needed to prevent treatment failure and improve the survival of B-cell lymphoma patients in future.

Background: This first-in-human phase 1 study (NCT04432597) evaluated the safety and recommended phase 2 dose (RP2D) of PRGN-2009, a gorilla adenoviral-vector targeting oncoproteins E6, E7 (human papillomavirus (HPV)16/18) and E5 (HPV16), as monotherapy (Arm 1A) and combined with the bifunctional TGF-β "trap"/anti-PD-L1 fusion protein bintrafusp alfa (BA; Arm 1B), in patients with recurrent/metastatic HPV-associated cancer.

Methods: Patients with ≥ 1 prior treatment (immunotherapy allowed) received PRGN-2009 (1 × 10¹¹ particle units or 5 × 10¹¹ particle units, subcutaneously) every 2 weeks for 3 doses, then every 4 weeks (Arm 1A), or PRGN-2009 (RP2D, schedule per Arm 1A) and BA (1200 mg, intravenously) every 2 weeks (Arm 1B). Primary endpoints were safety and RP2D of PRGN-2009; secondary objectives included overall response rate (ORR) and overall survival (OS).

Results: Seventeen patients were treated. In Arm 1A (n = 6) there were no dose limiting toxicities or grade 3/4 treatment-related adverse events (TRAEs), 5 × 10¹¹ PU was selected as RP2D, no responses were observed, and median OS (mOS) was 7.4 months (95% CI 2.9-26.8). In Arm 1B (n = 11), grade 3/4 TRAEs occurred in 27% of patients, ORR was 20% for all patients (22% in checkpoint-resistant patients), and mOS was 24.6 months (95% CI 9.6-not reached). Multifunctional HPV-specific T cells were increased or induced de novo in 80% of patients and not impacted by anti-vector antibodies. Higher serum IL-8 at baseline associated with shorter OS.

Conclusions: PRGN-2009 was well tolerated, and immune responses were observed to PRGN-2009. Encouraging anti-tumor activity and OS were noted in the combination with BA arm, consisting mainly of checkpoint-resistant patients. Trial Registration ClinicalTrials.gov Identifier: NCT04432597.