Oncoimmunology最新文献

Urothelial carcinoma (UC) remains a common cancer with significant morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) have helped revolutionize the treatment of UC, and there is growing evidence suggesting the crucial role of the gut microbiome in immune system function influences immunotherapy outcomes in this disease. Herein, we review the preclinical basis for how manipulation of the gut microbiome may alter the efficacy of immunotherapy for patients with cancer, highlight interventions optimizing gut microbiome diversity currently in use, review recent and ongoing clinical trials supporting the role of the gut microbiome in improving immunotherapy outcomes, and discuss clinical implications to improve outcomes for UC patients with immunotherapy in the real world. There is growing evidence that suggests that specific gut microbiome compositions significantly modulate the host immune system and response to ICIs. Early studies have shown that certain microbial taxa enhance antitumor immunity by influencing T cell priming, dendritic cell activation, and cytokine production. Fecal microbiota transplantation (FMT), probiotic supplementation, and dietary modulation have emerged as promising methods to alter microbiomes to improve immunotherapy outcomes. Taxa from positive immunotherapy responders across a variety of cancers demonstrate beneficial effects when transplanted into both treatment-naive or prior nonresponders. Increasing evidence suggests that the gut microbiome plays a crucial role in cancer care, particularly when patients are treated with immunotherapy. Future studies are needed to better understand the underlying mechanisms. While some studies are currently underway to explore gut manipulation for patients with UC, more studies are needed to investigate the potential to convert nonresponders into responders through microbiome manipulation.

Glioblastoma (GBM) remains therapeutically challenging due to treatment resistance and immunosuppression. Oncolytic virotherapy offers a promising strategy. This study engineered OVV-03, a novel HER2-armed oncolytic vesicular stomatitis virus (VSV), and evaluated its efficacy against GBM. OVV-03 demonstrated potent infectivity and cytotoxicity in GBM cell lines and patient-derived cells, inducing caspase-dependent apoptosis and suppressing proliferation/clonogenicity. In murine GBM models, OVV-03 significantly suppressed tumor growth, improved survival, and enhanced CD8⁺ T cell infiltration. Single-cell RNA sequencing revealed OVV-03 remodels the tumor immune microenvironment by boosting cytotoxic T cell activity and inhibiting immunosuppressive pathways, notably PD-L1/PD-1 signaling. Mechanistically, OVV-03 downregulated PD-L1 by inhibiting the JNK-c-Fos/c-Jun axis, reversible by TNF-α stimulation. Critically, OVV-03 synergized with B7H3- or HER2-targeted CAR-T cells, inducing superior tumor regression and prolonged survival in orthotopic models. These findings demonstrate that OVV-03 exerts potent antitumor effects through direct oncolysis and immune activation, including PD-L1 modulation. Its synergistic combination with CAR-T cells highlights OVV-03 as a highly promising oncolytic immunovirotherapy platform for GBM.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. HPV-negative HNSCC, arising in diverse upper airway mucosal niches, is particularly aggressive, with poor 5-y survival and a limited response to immune checkpoint inhibitors. A deeper understanding of the tumor-localized immune landscape is essential to uncover actionable immunotherapeutic targets. Here, we integrated two single-cell RNA sequencing (scRNA-seq) datasets from 29 samples totaling nearly 300,000 immune cells to dissect immune rewiring during tumor progression and lymph node metastasis in HPV-negative HNSCC. We identified distinct shifts in adaptive immune cell populations across 14 peripheral blood mononuclear cell (PBMC) and 21 tumor-infiltrating immune cell (TIC) states. Notably, TICs exhibited enriched interferon response and immunomodulatory gene signatures, in contrast to PBMCs, indicating tumor-specific immune imprinting. Ligand-receptor analysis revealed that immunosuppressive crosstalk between macrophages and cytotoxic cells was associated with advanced disease. To spatially validate these transcriptional states, we conducted multiplexed immunofluorescence profiling on nine locally invasive HPV-negative HNSCCs, all from the ventrolateral tongue mucosa. Spatial proteomics confirmed peritumoral enrichment of activated (CD107a⁺, ICOS⁺) NK and CD8⁺ T cells and intratumoral accumulation of exhausted (PD-1⁺, PD-L1⁺) phenotypes, mirroring pseudotime trajectories inferred from scRNA-seq. These findings highlight spatially localized cytotoxic cell exhaustion as a key immune evasion mechanism in HPV-negative HNSCC and underscore the value of integrating spatial and single-cell data to reveal therapeutic vulnerabilities.

Checkpoint inhibitors targeting PD-1/PD-L1 have revolutionized cancer immunotherapy, yet their efficacy in prostate cancer has been limited. We previously reported a clinical trial (NCT02499835) evaluating PD-1 blockade combined with an anti-tumor DNA vaccine, pTVG-HP (encoding prostatic acid phosphatase), in patients with metastatic castration-resistant prostate cancer. Decreases in serum prostate-specific antigen (PSA) levels were observed in 35% of patients, and 42% of patients developed immune-related adverse events (irAE). In long-term follow-up, any decrease in PSA or the development of an irAE was associated with prolonged overall survival (p = 0.009 or p = 0.006, respectively), suggesting a potential association between irAE and anti-tumor immunity. To evaluate this, tumor biopsies obtained pre- and post-treatment from 12 patients were evaluated by gene expression profiling and spatial protein analysis. Clinical responders (those with any decrease in PSA) presented with reduced checkpoint marker expression and increased expression of markers associated with dendritic cells, antigen presentation, and T-cell activation. These gene expression signatures highly overlapped with signatures from patients who experienced an irAE. Conversely, non-responders showed enrichment of immunosuppressive pathways, including elevated expression of VISTA and myeloid-derived suppressor cell (MDSC)-associated markers. Patients without irAE had increased expression of PARP. These findings suggest that patients experiencing irAEs can have immune responses to tumor irrespective of obvious anti-tumor efficacy, at least with these treatments, and underscore the importance of tumor-infiltrating professional antigen presenting cells and T-cell activation for successful immunotherapy. Moreover, our findings suggest that combining vaccines and PD-1 blockade with MDSC-targeting therapies, anti-VISTA, and/or anti-PARP therapies might be further explored.

Our laboratory specializes in the intratumoral (i.t.) delivery of virus nanoparticles (VNPs) that activate immune cells and modulate the tumor microenvironment (TME). For this study, we conjugated the CH401 peptide-containing B-cell, helper T-cell, and cytotoxic T-cell epitopes of HER2-to the plant cowpea mosaic virus (CPMV) and bacteriophage Qβ to develop vaccines for HER2⁺ cancer. In vivo studies confirmed that the CPMV_CH401 i.t. therapeutic vaccine candidate was successful in CT26-HER2 and MC38-HER2 tumor models through the induction of IgG2a antibodies, upregulation of Th1 cytokines, and activation of Th1 cells. On the other hand, the Qβ_CH401 i.t. therapeutic vaccine candidate induced IgG1 antibodies and a Th1/2 balanced response, which did not result in potent anti-tumor efficacy. This study highlights that different VNP carriers are differential in immune modulation and that CPMV_CH401, but not Qβ_CH401, is effective as an i.t. vaccine. We also learned that the subcutaneous prophylactic immunization route leads to stronger humoral immunity but fails to modulate the TME, limiting the anti-tumor efficacy. This study highlights that, combined with the HER2 epitope, the i.t. therapeutic approach has powerful anti-tumor capabilities. It induces therapeutic HER2 antibodies, immunomodulation of the TME, and T-cell responses against the tumor, making this a robust active immunotherapy regimen.

Adoptive therapy with CAR-T cells and systemic administration of bispecific T-cell engagers (TCE) have achieved unprecedented success in the treatment of relapsed/refractory (R/R) B-cell malignancies. However, high relapse rates remain a major challenge. STAb (Secretion of T cell-redirecting bispecific Antibodies)-T-cell immunotherapy represents a promising alternative by enabling both polyclonal T-cell recruitment and sustained bispecific antibody release. Here, we describe an evolution of STAb-T19 therapy, which has demonstrated superior outcomes to those of CAR-T-19 cells in preclinical models of B-ALL, on the basis of the simultaneous secretion of two bispecific antibodies: a CD19 × CD3 TCE and a PD-L1 × 4-1BB bsAb. The combined approach aims to increase the antitumor efficacy of STAb-T19 cells by blocking the PD-1/PD-L1 axis with conditional 4-1BB costimulation to ensure the long-term persistence of STAb-T cells. Preclinical data show that this combination improves cytotoxic activity and prolongs antileukemic efficacy compared with low-dose single STAb-T therapy. Our findings suggest that the integration of PD-L1 × 4-1BB bsAbs into STAb-T19 therapy may maximize efficacy, thereby opening a promising avenue to address resistance and relapse in B-ALL. Moreover, this approach may pave the way for the development of next-generation cell-based therapies for hematologic and solid malignancies.

This study contributes to the characterization of human macrophages in normal and pathological conditions such as cancer. We characterized a macrophage population expressing membrane-associated IL-18 (mIL-18) that shows peculiar proteomic, phenotypic, ultrastructural, and functional properties. mIL-18+ macrophages exhibit increased levels of key proteins involved in pathogen recognition, activation, migration, and endocytosis. They also display specialized functions in vesicle and actin filament transport and lipid metabolism, and have typical mitochondrial traits. Importantly, mIL-18+ cells dominate the peritoneal fluid of adult cancer patients and are present in the bone marrow of children with neuroblastoma. They express high levels of TREM2 but display heterogeneous FOLR2 expression, distinguishing distinct cell subsets with possibly different functions. Accordingly, in primary neuroblastomas, transcriptional signatures associated with mIL-18 expression show different prognostic values. Our data show that mIL-18+ macrophages, which are predominant across the tumor microenvironment, exhibit previously undetected heterogeneity, potentially impacting tumor progression in a variable manner.

The incorporation of the current immunotherapy, GD2-targeting monoclonal antibodies, into the standard of care has moderately improved clinical outcomes in children with high-risk neuroblastoma (HR-NB); however, overall survival remains low. More than 50% of patients with HR-NB are refractory to or eventually develop resistance to anti-GD2 treatment. HR-NBs are generally known to have a low tumor mutational burden, are immunologically cold and possess an immunosuppressive tumor microenvironment. Understanding the mechanisms of immune evasion may provide novel targets for improving the efficacy of immunotherapies for these immunologically cold HR-NBs. Here, utilizing immunocompetent mouse models of immunologically cold HR-NB, we revealed a novel function of IGF2BP1 in promoting the immune escape of neuroblastoma tumors. We demonstrate that neuroblastoma cell-specific knockdown of IGF2BP1 favorably alters the tumor microenvironment of HR-NBs, turning these "immunologically cold" tumors into an immunogenic type, thereby priming them for anti-GD2 therapy-induced immune responses. Downregulation of IGF2BP1 in NB cells decreased the number of immunosuppressive T-regulatory and dysfunctional/exhausted CD8+ T cells and promoted the accumulation of effector MHCII +  macrophages at the tumor site. Importantly, knockdown of IGF2BP1 along with anti-GD2 immunotherapy induced a synergistic immunogenic effect and achieved a potent antitumor response in an HR-NB mouse model, with increased accumulation of effector CD8+ T cells and CD86+  macrophages but decreased MDSC numbers in the tumor microenvironment. Thus, disrupting NB cancer cell IGF2BP1-mediated immunosuppression is a potential approach for improving the efficacy of anti-GD2 immunotherapy towards HR-NBs.