Journal for Immunotherapy of Cancer最新文献

Background: Challenges to developing immunotherapies for acute myeloid leukemia (AML) include the identification of suitable target antigens due to on-target-off-leukemia toxicity. CD70, expressed on AML bulk and leukemic stem cells with limited expression on healthy cells, has emerged as a promising target.

Methods: This study evaluated CD70 as a target for NK-cell-based immunotherapy using a sugar-engineered antibody (PF-08046040, SEA-CD70). CD70 surface expression was assessed in primary AML samples by multiparameter flow cytometry. The cytotoxic capacity of SEA-CD70 was analyzed through antibody-dependent cellular cytotoxicity (ADCC) assays using AML cell lines, primary AML samples, and a severe combined immunodeficiency (SCID) mouse xenograft model. The effects of cytokines on CD70 expression and ADCC were investigated by exposing AML cells to conditioned medium (CM) derived from activated T cells or recombinant cytokines.

Results: Flow cytometry revealed CD70 expression ranging from 0.2% to 89.6% (median=7.0%, n=86) in primary AML cells across genetic subgroups; this expression remained unchanged at relapse (median=3.9%, n=14). SEA-CD70 showed potent, dose-dependent cytotoxicity against AML cell lines, primary cells, and in an SCID mouse model, which correlated with CD70 expression levels. Notably, AML cells exposed to CM from activated T cells upregulated CD70. TNF-α was identified as the driver of CD70 upregulation, translating into enhanced ADCC against AML cells (cytotoxicity w/o TNF-α = 17.9% vs with TNF-α = 34.3%, n=13-15). Conversely, IFN-γ exposure led to reduced ADCC (cytotoxicity w/o IFN-γ = 17.9% vs with IFN-γ = 9.2%, n=15), which is attributed to increased expression of NK inhibitory receptor ligands (HLA-ABC, HLA-E). Blocking of the corresponding inhibitory NK receptors (KIR/CD158b and NKG2A) partially reversed this effect. Similar findings were observed with a CD33-directed antibody, indicating a universal resistance mechanism against ADCC-based immunotherapy in AML.

Conclusions: CD70 is a promising target for NK cell-based immunotherapy in AML. However, IFN-γ-dependent upregulation of HLA molecules on AML cells contributes to resistance to ADCC. These findings underscore the need for rationale combination strategies in clinical trials to overcome this inducible immune escape mechanism.

Common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) is a multifunctional scavenger receptor expressed on tumor-associated macrophages (TAMs). In a recent study published in the Journal for ImmunoTherapy of Cancer, Yu et al reported that CLEVER-1⁺ TAMs accumulate in advanced gastric cancer (GC), associate with poor prognosis, and contribute to resistance to chemoimmunotherapy. CLEVER-1 blockade using bexmarilimab reprogrammed TAMs toward a pro-inflammatory phenotype by suppressing peroxisome proliferator-activated receptor gamma (PPARγ)-driven lipid metabolism and enhancing antigen presentation and inflammatory cytokine secretion. CLEVER-1 blockade also synergized with anti-programmed cell death protein 1 (PD-1) therapy in ex vivo GC models, particularly in tumors enriched with CLEVER-1⁺ TAM. These findings identify CLEVER-1⁺ TAMs as both biomarker and functional mediator of anti-PD-1 therapy resistance, providing a rationale for combining bexmarilimab with immune checkpoint blockade in GC. In this commentary, we discuss the mechanistic significance, translational potential, and clinical prospects of CLEVER-1 blockade to overcome immunotherapy resistance in GC.

Background: Blinatumomab, inotuzumab or autologous anti-CD19 chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, tumor escape through antigenic modulation accounts for almost 40% of subsequent relapses. Multi-antigen targeting strategies should be developed, and it is urgent to identify new targets.

Methods: We investigated the extensive immunophenotyping of 13 BCP-ALL from pediatric patients by using the BioLegend Human Cell Surface Marker Screening Kit. Then, to assess whether targeting each antigen with monoclonal antibodies could lead to leukemic cell lysis, long-term antibody-dependent cellular cytotoxicity (ADCC) assays were performed using murine monoclonal antibodies and human T cells armed with murine CD16.

Results: 13 highly expressed antigens were selected. With the antibodies tested here, the most significant lysis was observed by targeting CD24 and CD156c. The double targeting of CD24-CD123 appeared to be even more effective. Triple targeting was associated with a reduction in ADCC activity.

Conclusion: CD24 therefore emerged as an effective target in BCP-ALL, and the combination of CD24 and CD123 as a potential effective double-targeting strategy. The combination of different recognition modalities (eg, a CAR and CD16) should be tested to determine whether it provides synergistic cytotoxic activity in triple targeting.

Background: T-cell exhaustion induced by the tumor microenvironment is an important factor in posing a major challenge to effective cancer immunotherapy. Immune checkpoint inhibitors aim to reverse T-cell exhaustion. However, the effectiveness of immune checkpoint inhibitors is often limited due to their off-target effects and single targets. Herein, we attempt to identify molecular targets that can regulate the expression of multiple immune checkpoints to reverse T-cell exhaustion.

Methods: NSG mice with xenotransplantation of human bladder cancer cells were used to investigate the function of nuclear paraspeckle assembly transcript 1 (NEAT1) in T-cell exhaustion. Chromatin isolation by RNA purification, chromatin immunoprecipitation, and luciferase assays was employed to investigate the molecular mechanisms by which NEAT1 regulates expression of target genes.

Results: NEAT1, a bladder cancer-related long non-coding RNA (lncRNA), promotes lactate production in tumor cells by binding to the lactate dehydrogenase A gene. This lactate production subsequently inhibits NEAT1 expression in CD8+T cells. Furthermore, NEAT1 in CD8+T cells plays a crucial role in modulating the immune response of CD8+T cells against tumor cells. Our findings indicate that NEAT1 regulates the expression of multiple immune checkpoint genes by directly binding to them and inhibiting transcription through the alteration of histone lactylation near transcriptional start sites, which affects RNA polymerase II recruitment.

Conclusions: lncRNA NEAT1 serves as a modulator of the antitumor response of CD8+T cells in the bladder tumor microenvironment and may represent a therapeutic target for reversing T-cell exhaustion.

Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer in Asian, Caucasian, and Hispanic populations and its aggressive form contributes to significant morbidity and mortality. Chronic ultraviolet B (UVB) exposure is a major environmental carcinogen that drives cSCC initiation, progression, and immune evasion. Regulatory T cells (Tregs) are known mediators of UVB-induced immunosuppression; however, their direct involvement in the establishment of cSCC remains elusive.

Methods: Flow cytometry was employed to quantify Treg populations in the skin and draining lymph nodes of UVB-exposed and untreated mice. The functional role of Tregs following UVB exposure was examined using a contact hypersensitivity assay, where Treg activity was modulated by anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4, anti-TIGIT, and anti-FR4 antibodies. The capacity of UVB to render mice susceptible to immunogenic cSCC tumor establishment was assessed under different UVB exposure regimens. Treg-modulating antibodies were administered following UVB treatment and prior to tumor implantation to explore whether UV-induced Treg manipulation can prevent cSCC tumor establishment.

Results: UVB irradiation for 5 consecutive days significantly increased the number of CD4⁺ Foxp3⁺ Tregs in both skin and skin-draining lymph nodes. These Tregs were shown to be suppressive in contact hypersensitivity assays. However, suppression was prevented following depletion of Tregs and/or avolition of their function using monoclonal antibodies. Consistently, chronic UVB exposure prior to tumor implantation permitted the establishment and growth of otherwise immunogenic cSCC tumors, which correlated with the expansion and recruitment of Tregs into the skin. Importantly, immunomodulation with anti-CTLA-4 or anti-FR4 after chronic UVB exposure effectively prevented cSCC establishment, indicating that the manipulation of UV-induced Tregs prevented the establishment and growth of immunogenic cSCC tumors.

Conclusion: Our findings show that the manipulation of UV-induced Tregs prevents early cSCC establishment. Thus, strategies aimed at modulating Treg function or abundance in the skin may represent a feasible therapeutic avenue for the prevention of cSCC tumor emergence in patients.

Genetically modified cell-based therapies hold transformative potential, particularly for patients with rare cancers and ultra-rare diseases. However, progress toward regulatory approval, reimbursement, and broad patient access is often constrained by misaligned regulatory, manufacturing, and financial frameworks that do not reflect the realities of treating small populations and low-throughput production models. Drawing on a collaborative white paper and public meeting convened by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy in May 2025, this commentary outlines three strategies to streamline regulatory pathways and enable timely, sustainable access: (1) flexible approaches to Chemistry, Manufacturing, and Controls requirements in small populations, (2) adaptable regulatory frameworks to support diverse manufacturing models, and (3) limited cost recovery mechanisms to bridge early access and development gaps. Recent regulatory and policy discussions have echoed these priorities, signaling an opportunity to align oversight with operational realities to advance innovation and access for patients in high-need settings.

Aging impairs antitumor immunity and may reduce the efficacy of immune checkpoint inhibitors (ICIs). However, the underlying mechanisms remain unclear. Building on our recent findings, we review three key mechanisms of CD8⁺ T-cell aging: elevated T-cell receptor (TCR) activation thresholds, mitochondrial dysfunction, and disruption of proteostasis. Studies in aged mice have revealed that aged naïve T cells exhibit defective priming due to increased CD45 expression, which raises the TCR activation threshold and restricts effector differentiation. Aging also impairs mitochondrial metabolism, particularly fatty acid oxidation. Furthermore, we highlight the role of proteostasis collapse, including defective autophagy and increased endoplasmic reticulum stress, as a contributor to T-cell dysfunction. Spermidine, a polyamine that declines with age, has the potential to modulate both mitochondrial function and proteostasis. Its supplementation has been shown to improve programmed cell death-1 blockade responsiveness in aged mice. Although clinical studies in humans have yielded inconsistent results regarding the effect of chronological age on ICI efficacy, identifying patients with "age-related" immune microenvironments may enable stratified therapeutic approaches based on insights from preclinical aging models.

Background: Enhancing immunogenicity and antigen-presentation efficiency is critical for tumor vaccine development. While yeast-surface glycoprotein side chains can improve antigen presentation, their ability to deliver tumor antigens remains limited.

Methods: The composite carbon nanopolymers (Asparagine-N-acetylglucosamine-Mannose derived carbon nanopolymers, ANM-NPs) mimicking yeast-surface glycans side chains were prepared using asparagine, N-acetylglucosamine and mannose as precursors via microwave-assisted synthesis method. Combined with whole-cell tumor antigen (T-Ag), the vaccine ANM-NPs@T-Ag was prepared. The expression levels of major histocompatibility complex-II, CD80, and CD86 were analyzed by flow cytometry to evaluate the enhancement of antigen presentation. The antitumor efficacy of ANM-NPs@T-Ag was assessed by H22-LUC and B16-F10-LUC tumor-bearing models.

Results: ANM-NPs have an average particle size of approximately 21.69 nm and exhibit good stability. Compared with traditional aluminum adjuvants, ANM-NPs demonstrate superior efficacy in promoting antigen presentation and immune activation. ANM-NPs effectively stimulated innate immunity, facilitated immune cell infiltration, and enhanced adaptive immune responses. The vaccine ANM-NPs@T-Ag targeted dendritic cells via mannose receptors, activating the lectin pathway, improving complement opsonization, and enhancing antigen presentation. ANM-NPs@T-Ag stimulated cellular/humoral immunity, increased tumor-specific IgG, and inhibited tumor growth. ANM-NPs@T-Ag also enhanced the antitumor effect of α-PD-1 (programmed cell death protein-1).

Conclusion: These findings demonstrate that ANM-NPs can serve as a potential vaccine adjuvant, and ANM-NPs@T-Ag represents a promising tumor vaccine candidate.Cite Now.

Background: Programmed cell death protein-1 (PD-1) blockade has shown promising clinical efficacy in hepatocellular carcinoma (HCC), yet the underlying immunological mechanisms governing response and resistance remain unclear. This study aimed to delineate the temporal and spatial dynamics of T-cell clonotypes and their relationship with pathological response in neoadjuvant PD-1 blockade therapy in HCC. By integrating T-cell receptor (TCR) repertoire analysis with transcriptomic profiling, we sought to elucidate the immune landscape alterations associated with treatment outcomes.

Methods: We analyzed longitudinal, matched tumor and blood samples from our previous clinical trial (NCT05471674), encompassing 114 specimens, including pre-nivolumab tumor biopsies, post-treatment resected tumors, adjacent non-tumorous livers, and peripheral blood collected before, after, and during follow-up from 19 treatment-naïve HCC. TCR clonality, diversity, and transcriptomic signatures were assessed to characterize immune responses.

Results: Elevated clonality of intratumoral TCR clonotypes (ITCs) post-treatment correlated with increased pathological tumor necrosis, predominantly driven by the most abundant top 1% ITCs. These dominant clonotypes occupied a significantly larger clonal space and demonstrated increased spatial sharing across tumor, non-tumorous liver, and peripheral blood compartments in nivolumab responders (nivo-Rs). Shared clonotypes were positively associated with tumor necrosis extent and cytolytic activity, suggesting active immune engagement. Post-treatment, shared clonotypes exhibited peripheral expansion and greater intratumoral dominance in nivo-Rs, whereas tumor unique intratumoral TCR clonotypes (ITCs) remained prevalent in non-responders (nivo-NRs). These divergent patterns were linked to higher chemokine expression within the tumor microenvironment of nivo-Rs and impaired human leukocyte antigen (HLA) class II antigen presentation in nivo-NRs, indicating distinct immune landscape configurations influencing therapeutic response.

Conclusions: Our findings demonstrate that the peripheral infiltration and expansion of high-frequency intratumoral T-cell clonotypes are critical drivers of pathological response to neoadjuvant PD-1 blockade in HCC, highlighting potential immune biomarkers and therapeutic targets to enhance immunotherapy efficacy.