Cancer Immunology, Immunotherapy最新文献

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.

Lymph nodes are the most common metastasis sites for tumor cells, which are intimately linked to patient prognosis. It has been reported that cancer cells can upregulate CC Chemokine Receptor 7 (CCR7) expression and hijack its normal functions, enabling them to migrate along the gradient of CCL19 and CCL21 toward the lymph nodes and colonies as the initial stage of distant metastasis. In tumor patients, the metastatic tumor in the lymph nodes exhibited higher expression of CCR7, as well as inhibitory immune checkpoints PD-1, LAG-3, and TIM-3 compared to the primary tumors with the analysis of TCGA and GEO databases. Also, in mouse tumor model, tumor cells with elevated CCR7 expression were more susceptible to develop popliteal lymph node metastasis. Subsequently, we successfully identified a CCR7 binding peptide TC6 by phage display biopanning, which specifically blocks the interaction of CCR7/CCL19 and CCR7/CCL21. Further, the D-amino acids were introduced to substitute the N- and C-terminus of TC6 peptide to obtain the proteolysis-resistant TC6-D3 peptide, which decreased tumor cell migration in vitro via ERK1/2 pathway and inhibited tumor growth and lymph nodes metastasis in vivo, as well as effectively restored T cells cytotoxicity in both primary tumors and lymph nodes. In conclusion, CCR7 promoted tumor cell metastasis to lymph node and inhibited the anti-tumor immune responses in lymph nodes. Specific blockade of the CCR7 pathway with TC6-D3 peptide can significantly reduce lymph node tumor burden, promoting CD8⁺ T cell infiltration in primary tumors, meanwhile, enhancing anti-tumor immune responses in lymph nodes.

Purpose: Appropriate local therapy may provide survival benefits in oligometastatic non-small cell lung cancer (NSCLC) patients receiving chemotherapy or targeted therapy. However, its roles in immunotherapy-treated patients have not been fully understood.

Methods: PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients were enrolled in a prospective multi-center observational study (NCT04766515) from September 2020 to March 2023. Those without driver mutations, with measurable disease and harboring oligometastatic disease were included. Progression-free survival (PFS) and overall survival (OS) were compared between those with or without early local therapy (eLT). Moreover, eLT performed within or after 1 month of the initiation of PD-1/PD-L1 inhibitors was defined as concurrent- or sequential-LT, respectively. While, eLT targeting partial or all of the tumor lesions, was described as partial- or all-LT, respectively.

Results: Among the 180 patients identified, eLT was performed in 44, including concurrent-LT in 25 and all-LT in 19, respectively. With a median follow-up of 19.40 months, progressive disease occurred in 95 of the 136 patients without eLT. Compared to those without eLT, patients receiving eLT had significantly longer PFS (HR = 0.40, 95% CI 0.27-0.59, p < 0.0001) and OS (HR = 0.43, 95% CI 0.24-0.76, p = 0.02). Moreover, eLT was associated with improved survival after Cox analyses and propensity score matching. Meanwhile, sequential-LT, as well as all-LT, was associated with longer OS, when compared with concurrent-LT or partial-LT, respectively.

Conclusions: Early local therapy, especially those performed after effective systemic therapy and targeting all tumor lesions, may prolong patient's survival in PD-1/PD-L1 inhibitor-treated oligometastatic NSCLC.

BRAF-mutated colorectal cancer correlates with poor prognosis and limited response to standard treatments. Combining immune checkpoint inhibitors with BRAF/MEK inhibitors shows promise against BRAF-mutant melanoma in both preclinical and clinical trials. Therefore, we hypothesized that the treatment would be effective against BRAF-mutant colorectal cancer. In this study, we assessed the efficacy of combining immune checkpoint inhibitors with BRAF and/or MEK inhibitors in BRAF-mutant colorectal cancers. We treated BRAF V600E colorectal cancer cells HT-29 and SNU-1235 with encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) and assessed the degrees of MAPK inhibition, JAK/STAT inhibition, cell viability, apoptosis, and the expression of antigen presenting machinery. We also inoculated HT-29 cells into mice and treated them with an immune checkpoint inhibitor (durvalumab), encorafenib, and binimetinib for 4 weeks. We found that treatment with BRAF inhibitor, MEK inhibitor, or their combination led to significant tumor growth reduction, along with the MAPK and JAK/STAT pathway inhibition, antigen presenting machinery induction, and cytotoxic T cell activation. Our study demonstrates the potential effectiveness of combining immune checkpoint inhibitors with BRAF or MEK inhibitors for BRAF-mutated colorectal cancers.