Cancer Immunology, Immunotherapy最新文献

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by marrow fibrosis, splenomegaly, constitutional symptoms and cytopenia with a proinflammatory and profibrotic cytokine phenotype involving the JAK-STAT pathway. Ruxolitinib is a JAK 1/2 inhibitor with proven efficacy on splenomegaly and constitutional symptoms, but it does not reverse fibrosis or the risk of leukemic transformation. While hematopoietic stem cell transplantation remains the only curative approach, it is still associated with a relatively high non-relapse mortality (NRM) rate, partly due to GVHD. The potential role of ruxolitinib or its withdrawal on NRM remains to be elucidated, and inflammatory cytokines might be implicated. In this report, we compared cytokine profiles in patients with myelofibrosis not treated with ruxolitinib (n = 18) or who received ruxolitinib and stopped it at conditioning regimen initiation (n = 53), at three different time points. At baseline, MF patients without ruxolitinib had increased inflammatory cytokine levels (CD25, REG3A, IL18 and ST2) as compared to MF patients on ruxolitinib. On day 0 and week 1 post-transplantation, levels of these cytokines were similar with and without ruxolitinib. On the other hand, cytokine levels at baseline did not predict grades 2-4 acute GVHD or hyperacute GVHD. These findings suggest that baseline cytokine profile in MF patients does not impact the risk of GVHD. Stopping ruxolitinib just before conditioning regimen may not influence GVHD risk more than in MF patients who have not received ruxolitinib. The potential benefit of a later ruxolitinib discontinuation on D0 or after transplantation ruxolitinib requires further investigation.

Background: Glycolysis, a classic characteristic of cancer cells, can drive cancer progression by generating lactate, which play as a key immunosuppressive mediator. Currently, ubiquitin-specific proteases 5 (USP5) has been demonstrated to facilitate tumor cell survival in multiple myeloma (MM), whereas whether USP5 was involved in glycolysis-lactate production pathway and immunosuppressive microenvironment formation in MM remain unknown.

Methods: The gene and protein expression characteristics were assessed via qRT-PCR and western blot. MM cell survival was determined by CCK-8 and flow cytometry analysis. Glycolysis was evaluated by examining glucose uptake, lactate production and ATP level via corresponding kits. Tumor-associated macrophages polarization was tested via measurement of M1/M2-like macrophage markers using qRT-PCR and flow cytometry methods. Dual-luciferase reporter, chromatin immunoprecipitation and co-immunoprecipitation assays were conducted to verified molecular relationship. Xenograft model was used for verified cellular findings.

Results: USP5 was abnormally overexpressed in MM patients and cell lines. Knockdown of USP5 could restrain MM cell survival and glycolysis activity, thus reducing lactate-mediated immunosuppressive M2-like macrophage polarization in vitro and in vivo, whereas overexpression of USP5 play opposite impacts. Mechanistically, USP5 could downregulate the ubiquitination modification of STAT to stabilize STAT2 protein, thus activating PFKFB4 transcription. Moreover, STAT2 could overturn the regulatory role of USP5 on MM cell survival, glycolysis and lactate-mediated immunosuppressive M2-like macrophage polarization.

Conclusion: These findings elucidated that USP5 served as a regulator of glycolysis-lactate to stimulate M2-like macrophage formation by regulating STAT2-PFKFB4 signaling, which supported that USP5 could be a viable therapeutic target of MM treatment.

Introduction: Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive subtype of soft tissue sarcoma, characterized by limited treatment options and poor prognosis. Despite surgical resection being the only potentially curative treatment for localized DDLPS, the recurrence rate remains high, and systemic chemotherapy, typically anthracycline-based, shows limited efficacy in advanced stages. While immune checkpoint inhibitors (ICIs) have shown promise in various sarcoma subtypes, including DDLPS, their role as a first-line treatment remains unclear.

Methods: We conducted a systematic meta-analysis to evaluate the efficacy of ICIs in treating patients with DDLPS. A total of 25 studies encompassing 245 patients were included. Data on overall response rate (ORR), progression-free survival, and grade III-V treatment-related adverse events were analyzed. We assessed treatment efficacy based on the line of therapy and treatment regimens, including ICI monotherapy, dual ICI therapy, and ICI combinations with other modalities.

Results: The pooled ORR for all ICI-based treatments was 7%. First-line ICI therapy yielded a significantly higher ORR of 22%, compared to 4% in later-line treatment. The combination of ICI with anthracyclines demonstrated the highest ORR of 52%. In contrast, ICI regimens combined with trabectedin or other agents showed limited efficacy. Sensitivity analysis confirmed the stability of results, and publication bias was not detected.

Conclusion: This meta-analysis supports the potential role of ICIs, particularly in combination with anthracyclines, as a first-line therapeutic strategy for DDLPS. These results provide a foundation for future prospective studies aimed at optimizing immunotherapy approaches for this rare and challenging malignancy.

Background: The prognostic nutrition index (PNI) has recently been highlighted as a predictor of immune checkpoint (IC) inhibitor efficacy in gastric cancer (GC). Although LAG3, an IC molecule, has gained considerable attention, its association with PNI remains unexplored.

Materials and methods: We retrospectively analyzed clinical data from 796 GC patients who underwent radical gastrectomy to identify which previously reported nutritional index had the greatest impact on prognosis. Single-cell RNA sequencing was performed on 38 GC tissues, and multiplex immunofluorescence staining was conducted on 59 GC tissues to evaluate the relationship between nutritional indices and IC molecule expression in cytotoxic CD8-positive T cells.

Results: A low preoperative PNI was identified as the strongest predictor of poor prognosis among the nutritional indices in GC patients. The expression of not only PDCD1 (encoding PD1) but also LAG3 in cytotoxic CD8-positive T cells was significantly higher in GC with low PNI compared to those with high PNI. Among cytotoxic CD8-positive T cells, the proportion of LAG3-positive cells was greater than that of PDCD1-positive cells, particularly in GC with low PNI, and most LAG3-positive cells did not co-express PDCD1. Additionally, the expression of MHC class II, a ligand for LAG3, was higher in GC cells with high levels of epithelial-mesenchymal transition-related molecules in GC with low PNI compared to those with high PNI.

Conclusions: PNI can reflect LAG3 expression in cytotoxic CD8-positive T cells and MHC class II expression in GC cells.

Introduction: Esophageal cancer (EC) remains highly lethal due to tumor microenvironment (TME)-mediated immune evasion. While natural killer (NK) cells are central to antitumor immunity, their functional states in EC are poorly characterized.

Methods: We integrated bulk RNA-seq (TCGA/GEO) and single-cell data to construct an NK cell-derived prognostic signature (NK score) via LASSO-Cox regression. Immunofluorescence was applied to assess the clinical relevance of SAMD3 + NK cells in EC. Using both xenograft mouse models and in vitro co-culture procedures, the impact of SAMD3 on NK cell function was confirmed.

Results: In EC patients, the prognostic NK score-which is generated from important NK cell markers including SAMD3-was substantially correlated with a worse chance of survival. NK cells within the TME had significant levels of SAMD3 expression, as seen by immunofluorescence labeling. Moreover, NK cells with SAMD3 knockdown exhibited enhanced antitumor activity, leading to decreased tumor development in the xenograft model.

Discussion: Our results demonstrate the predictive significance of NK cell markers in EC and pinpoint SAMD3 as a critical modulator of NK cell activity. We pioneer SAMD3 + NK cells as architects of TME immunosuppression in EC. Our findings nominate SAMD3 inhibition as a combinatorial strategy to overcome immune checkpoint blockade resistance.

Glioblastoma (GBM) is the most aggressive and malignant type of primary brain tumor, with a median survival time of less than two years and a uniformly poor prognosis, despite multimodal therapeutic approaches, which highlights an urgent need for novel therapeutic targets. In this study, by integrative multi-omics analysis from CPTAC database, DepMap database and seven independent GBM cohorts, four hub genes (CD44, SURF4, IGSF3 and RALGAPA1) were identified as essential genes regulated by cancer driver genes with robust prognostic value. GBM multi-omics data from public and in-house cohorts validated that CD44 and SURF4 might be synthetic lethal partners of loss-of-function tumor suppressor genes. Analysis for immune-related pathway activity revealed complex regulation relationships of the four hub genes in tumor microenvironment (TME). Further investigation on SURF4 in pathway activity, immune therapy response and drug sensitivity proposed that SURF4 emerged as a promising therapeutic target for GBM, even for pan-cancer. Pan-cancer multi-omics exploration suggested that RALGAPA1 may be a tumor suppressor gene. By screening the first-generation and second-generation DepMap database, four genes (CCDC106, GAL3ST1, GDI2 and HSF1) might be considered as synthetic targets after mutation of RALGAPA1 as a tumor suppressor gene.

The MITO-END3 trial compared carboplatin and paclitaxel (CP) with avelumab plus carboplatin and paclitaxel (CPA) as first-line treatment in endometrial cancer (EC) patients and demonstrated a significant interaction between avelumab response and mismatch repair status. To investigate prognostic/predictive biomarker, 29 MITO-END3-EC patients were evaluated at pretreatment (B1) and at the end of CP/CPA treatment (B2) for peripheral myeloid-derived suppressor cells (MDSC) and Tregs. At B2, effector Tregs frequency was significantly higher in patients treated with CPA as compared to CP (p = 0.038). Both treatments (CP/CPA) induced significant decrease in peripheral M-MDSC (- 5.41%) in TCGA 2-MSI-high as compared to TCGA-category 4 tumors (p = 0.004). In accordance, both treatments induced M-MDSCs (+ 5.34%) in MSS patients as compared to MSI-high patients (p = 0.001). Moreover, in a subgroup of patients, primary tumors were highly infiltrated by M-MDSCs in MSS as compared to MSI-high ECs. A post hoc analysis displayed higher frequency of M-MDSCs (p = 0.020) and lower frequency of CD4+ (p < 0.005) at pretreatment in EC patients as compared to healthy donors. In conclusion, the peripheral evaluation of MDSCs and Tregs correlated with molecular features in EC treated with CP/CPA and may add insights in identifying EC patients responder to first-line chemo/chemo-immunotherapy.

Background: Immune checkpoint inhibitors (ICIs) offer durable progression-free survival (PFS) benefit in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, the predictors of long-term PFS (LTPFS) remain unclear.

Methods: Advanced NSCLC patients receiving first-line ICIs monotherapy at Guangdong Lung Cancer Institute between December 2017 and August 2022 were identified. Predictive value of different characteristics was evaluated in LTPFS (PFS ≥ 24 months) compared with short-term PFS (STPFS, PFS ≤ 3 months). Circulating cytokine levels were evaluated in paired peripheral blood samples collected before and after ICIs treatment.

Results: Among 202 patients identified and 171 included (median follow-up: 41.0 months), 44 (25.7%) experienced LTPFS, associated with a 5-year overall survival (OS) rate of 81.2%. Squamous NSCLC, intermediate or poor lung immune prognostic index (LIPI) score, and liver metastases, were negatively associated with LTPFS. High tumor mutational burden (TMB, ≥ 10 mutations/megabase) was enriched in LTPFS compared to STPFS (P = 0.002). Patients with both high TMB and PD-L1 demonstrated the greatest survival benefit from first-line ICIs monotherapy (median PFS: 24.5 months, median OS: 67.0 months). Thirty-eight peripheral blood samples were collected before and after ICIs treatment from 10 patients with LTPFS and 9 with STPFS, which revealed increased CCL11 (P = 0.013) and decreased IL1RA (P = 0.001) and IL17A (P = 0.003) levels in LTPFS after ICIs treatment.

Conclusion: Distinct clinical characteristics, including TMB, PD-L1, pathologic subtypes, LIPI score, number of organs involved, metastatic sites, and dynamic circulating cytokines profile features, can distinguish NSCLC patients achieving LTPFS from those with STPFS following first-line ICIs monotherapy.

We report a long-lasting response to the immune checkpoint inhibitor nivolumab in combination with regional hyperthermia (RHT) in a patient with recurrent metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) and negative programmed death ligand 1 (PD-L1) expression. Treatment was well tolerated with no local side effects. Tumor-related symptoms in the orbital and masticator area gradually decreased under treatment with nivolumab and RHT. Over the course of treatment, magnetic resonance imaging (MRI) showed a local tumor control in the heated tumor areas, while metastatic lesions developed in areas outside of the RHT field. This is the first case report demonstrating the feasibility and clinical potential of the addition of RHT in this patient collective with poor outcomes and low response rates to immune checkpoint inhibitors. RHT might be an additional tool to activate an immunogenic milieu responsive to immune checkpoint inhibitors.