Journal for Immunotherapy of Cancer最新文献

Background: Colorectal cancer often develops from adenomas over years, necessitating early intervention. Myeloid-derived suppressor cells (MDSCs) are major immune suppressive cell types in colon cancer development from adenomas through early inflammation-induced emergency myelopoiesis. Cannabidiol (CBD) is reported to function in psychosis, coronavirus infection and some cancers through immune regulation. However, its target and underlying mechanisms in colorectal adenomas are unknown.

Methods: The antitumor effect of CBD was validated in two classical colorectal adenomas models including azoxymethane (AOM)/dextran sulfate sodium salt (DSS) induced mice model and high-fat fed Apc^min/+ mice model. Single-cell RNA sequencing was used to identified the immune environment change after CBD treatment in mice colorectal adenomas. Target responsive accessibility profiling was used to find the target of CBD in MDSCs. Subsequently, multiple immunology assays and molecular biology experiment were employed to explore the adenomas prevention mechanisms of CBD.

Results: Here, we found that CBD prevented the incidence of colorectal adenomas in AOM/DSS model and high-fat diet fed Apc^min/+ mice model. Our single-cell RNA sequencing data and the results of immunofluorescence revealed that CBD treatment significantly decreased the number of MDSCs in both two colon adenomas models. Mechanistically, CBD bound to the guanine nucleotide exchange factor domain of EEF1B2, inhibiting its function in translational elongation and subsequent C/EBPβ synthesis. This disruption suppressed the differentiation and generation of MDSCs, leading to enhanced T-cell activation and prevention of colorectal adenoma progression.

Conclusion: Our findings reveal EEF1B2-mediated C/EBPβ protein synthesis as a crucial pathway in MDSC generation and highlight the potential of CBD as an early intervention strategy for colorectal adenomas.

Immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in patients with advanced malignancies. However, their association with immune thrombocytopenia (ITP) poses a critical risk of severe hemorrhage and necessitates treatment discontinuation. The precise molecular mechanisms underlying ICI-associated ITP remain largely unclear, critically impeding the development of predictive biomarkers and targeted therapeutic strategies. Here, we present a case report of an elderly patient with stage IV gastric adenocarcinoma who developed recurrent ITP following programmed death receptor-1 (PD-1) inhibitor serplulimab, trastuzumab and chemotherapy. Notably, longitudinal peripheral blood mononuclear cell samples were collected and subjected to transcriptomic profiling before and after two distinct ITP episodes: the initial occurrence and a recurrence triggered by PD-1 inhibitor rechallenge, providing matched time-resolved data for mechanistic analysis. Our findings demonstrate that ICIs-induced ITP involves a dual pathogenic mechanism combining immune-mediated platelet destruction and intrinsic megakaryopoietic impairment providing a novel conceptual framework for understanding this immunotherapy complication. And this represents the first prospective longitudinal investigation combining serial biospecimen collection with transcriptomic profiling (RNA sequencing) to elucidate mechanisms underlying ICIs-induced ITP.

Background: Tumor neoantigen vaccines typically require multiple prime-boost immunizations over several weeks or even months to elicit sufficient neoantigen-specific T-cell responses, which greatly limits their effectiveness against rapidly progressing cancers, such as hepatocellular carcinoma.

Methods: Here, we developed a functionalized alginate scaffold for T-cell activation as an artificial lymph node (FAST-LN) to rapidly and efficiently generate tumor neoantigen-specific T cells in vivo. The FAST-LN consists of an alginate scaffold crosslinked with calcium ions and hyaluronic acids conjugated with anti-TIM-3 (T cell immunoglobulin and mucin domain-containing protein-3) antibodies, then incorporates tumor neoantigen-encoding adenoviral vaccines, dendritic cells (DCs), and various cytokines (C-C motif chemokine ligand 21 (CCL21), interleukin (IL)-2, IL-4, and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)) that maintain DC maturation and recruit T cells for antigen presentation.

Results: This design facilitates efficient DC-T cell interactions within FAST-LN, enabling rapid generation of neoantigen-specific T cells for antitumor responses. In vivo antitumor studies demonstrated superior therapeutic efficacy of FAST-LN over traditional vaccines in mouse tumor models. Mechanistically, FAST-LN significantly enhanced tumor infiltration of CD8⁺ T cells, Th1 cells and macrophages, orchestrating robust antitumor responses.

Conclusions: Our results demonstrate that implantable FAST-LN rapidly induces tumor neoantigen-specific T cells in vivo, offering a promising strategy for neoantigen-based cancer immunotherapy.

Background: KRAS is one of the most frequently mutated genes in colorectal cancer (CRC) and plays a crucial role in tumorigenesis, progression, immune evasion, and treatment resistance. The pronounced heterogeneity within KRAS-mutant CRC highlights the urgent need for more precise and personalized therapeutic approaches.

Methods: To investigate this heterogeneity, we employed single-cell RNA sequencing and spatial transcriptomics to comprehensively characterize the tumor microenvironment of KRAS-mutant CRC. Data preprocessing and clustering were performed using Scanpy. Spatial cell-type deconvolution was conducted via Cell2location, whereas intercellular communication and spatial dependencies were analyzed using CellChat, MISTy, and stLearn.

Results: Our analyses revealed that KRAS-mutant tumor epithelial cells recruit Mono_S100A8 monocytes via the MDK_SDC4 signaling axis. Concurrently, surrounding Fib_CTHRC1 fibroblasts secrete collagen, which interacts with integrin receptors on KRAS-mutant epithelial cells and contributes to the exclusion of lymphocyte infiltration.

Conclusion: These cellular components collaboratively established an immunosuppressive spatial niche. These findings offer novel theoretical insights and potential targets for the development of immunoregulatory strategies tailored to KRAS-mutant CRC.

Background: Chimeric antigen receptor (CAR)-T cell therapy has been successful for the treatment of hematological cancers but less effective against solid tumors, a phenomenon that results from the immunosuppressive nature of the tumor microenvironment. As a strategy to improve the treatment of solid tumors, we applied CAR therapy to dendritic cells (DCs) to generate CAR-DCs. The CAR targeted the human epidermal growth factor receptor 2 (HER2) which is overexpressed in breast cancer to defeat the immunosuppressive nature of the tumor microenvironment.

Methods: CAR-DCs were generated by lentiviral vector transduction of SAMHD1 knock-out murine bone marrow-derived DCs. The vectors coexpressed CD40L and a soluble form of programmed cell death 1 (PD-1), a checkpoint inhibitor. To increase the durability of CAR-DCs, a gene encoding the cytokine GM-CSF was introduced into the CAR vector. The CAR-DCs were injected into mice bearing B16.HER2 melanoma tumors. Tumor growth was measured, and T cell functionality was determined by IFNγ expression and in vitro cytolytic assay.

Results: CAR-DCs suppressed the growth of B16.HER2 tumors and induced the proliferation and activation of tumor-infiltrating cytolytic CD8+T cells. The PD-1 checkpoint inhibitor further augmented the antitumor response and prevented T cell exhaustion. Vectored expression of GM-CSF increased the durability of the antitumor response.

Conclusions: CAR-DCs could be an effective strategy for therapies against solid tumors that should be further explored. The approach relies on the antigen-presenting ability of DCs and their role in T cell activation and can be coupled with checkpoint inhibition in place of monoclonal antibody treatment.

Background: Immunotherapy is considered a promising treatment approach for advanced biliary tract cancers (BTCs), but only a small number of patients can respond to immunotherapy. This study aimed to develop and validate a clinical-radiomics nomogram integrating radiomic features from lymph nodes (LNs) for predicting immunotherapy efficacy in advanced BTCs.

Methods: A total of 258 patients with advanced BTCs were enrolled, comprising 206 patients in the retrospective cohort and 52 patients in the prospective cohort. Radiomic features were extracted from the LNs. The maximum relevance and minimum redundancy and least absolute shrinkage and selection operator were used to develop the radiomics signature (Rad-score). Univariate analysis and multivariate logistic regression (LR) were used to construct the clinical model. A clinical-radiomics nomogram was constructed using LR. The performance of all the models was analyzed using receiver operating characteristic curves.

Results: Nine radiomic features were combined to construct the Rad-score. The nomogram incorporated the six clinical parameters and the Rad-score, and achieved the best discriminative ability with the areas under the curve (AUCs) of 0.899, 0.843 and 0.874 in the training, validation and testing cohorts. The clinical model showed better predictive performance than the Rad-score with the AUCs of 0.834, 0.878 and 0.740 in the training, validation and testing cohorts. The calibration curve and Brier score indicated the goodness-of-fit of the nomogram. Patients with higher nomogram scores had better overall survival (OS) and progression-free survival (PFS) in comparison to those with low scores.

Conclusion: The clinical-radiomics nomogram showed promising performance for predicting the response to immunotherapy in patients with advanced BTCs.

Background: Mitochondrial antiviral signaling protein (MAVS), a central adaptor in cytosolic RNA sensing, is critical for antitumor innate immunity and maintains mitochondrial homeostasis via its mitochondrial localization. Mitochondrial dysfunction acts as a key driver and amplifier of the senescence-associated secretory phenotype (SASP), a double-edged sword in tumor progression. However, whether tumor-intrinsic MAVS can regulate antitumor immunity via cellular senescence independently of its well-established interferon signaling remains unclear.

Methods: Our study employed an integrated strategy. Clinically, we profiled MAVS expression and its association with prognosis and immune infiltration in renal tumor specimens. Mechanistic insights into tumor-intrinsic MAVS were gained through a battery of techniques spanning quantitative PCR, immunoblotting, RNA sequencing, senescence and mitochondrial function assays, confocal imaging, immunohistochemical, mass spectrometry, and co-immunoprecipitation. In vivo, we used MAVS-deficient models combined with CD8⁺ T-cell depletion, programmed cell death protein-1 (PD-1) blockade, or reactive oxygen species (ROS) scavenging by N-acetylcysteine (NAC), with immune infiltration characterized by flow cytometry.

Results: Clinical evidence links elevated MAVS expression in renal tumors to poor prognosis and diminished CD8⁺ T-cell infiltration. Strikingly, tumor-intrinsic MAVS deficiency curbed malignant progression by triggering cellular senescence and fostering a permissive niche for CD8⁺ T-cell activation and recruitment. Mechanistically, MAVS orchestrates mitochondrial integrity by co-localizing with and stabilizing chemokine-like factor-like MARVEL transmembrane domain-containing 6 (CMTM6), thereby shielding it from lysosomal degradation. Disruption of this axis provoked mitochondrial dysfunction and ROS accumulation, culminating in senescence and an SASP marked by chemokine C-C motif ligand 3 (CCL3). Thus, despite dampening canonical innate immune signaling, MAVS deletion unleashed potent antitumor immunity via CCL3-mediated CD8⁺ T-cell recruitment, an effect abolished by CD8⁺ T-cell depletion or ROS scavenging with NAC. Leveraging this paradigm, we demonstrated that tumor-specific MAVS deficiency acts synergistically with PD-1 blockade to achieve robust therapeutic efficacy.

Conclusions: Our findings establish the tumor-intrinsic MAVS/CMTM6/CCL3 axis as a previously unrecognized critical regulator of senescence-driven antitumor immunity in renal carcinoma. Therapeutic targeting of this axis presents a promising strategy to curtail tumor progression and potentiate immunotherapy.

Background: Immunotherapies have revolutionized cancer care in recent decades, but approved therapies often fail and currently only target specific steps in the generation of anti-cancer immune responses. Notably, the majority of approved immunotherapies do not target antigen processing and presentation, which are key steps in the development of immune responses and harbor potential as targets to improve immunotherapy. Here, we hypothesize that tumor-mediated alterations in cytokine concentrations alter antigen presentation, which can be normalized by locoregional cytokine delivery or targeted immunological adjuvant delivery.

Methods: We used mouse models of breast cancer, with analysis by flow cytometry, immunofluorescence, confocal imaging, and single-cell RNA sequencing to address the impacts of tumors on locoregional antigen presentation, along with mechanisms to remedy these impacts.

Results: Here, we demonstrate that breast tumors induce locoregional impairments in dendritic cell antigen presentation that limits anti-cancer antigen-specific T cell responses. Antigen processing was not impaired in dendritic cells within the tumor-draining lymph node. A reduction of the cytokine IL-1β in tumor-draining lymph nodes was responsible for impairments in antigen presentation by dendritic cells. As such, we tested the ability of dendritic cells in lymph nodes at various distances from the primary tumor to be activated utilizing an antigen-agnostic immunological adjuvant delivery strategy. We observed improved antitumor T cell responses when immunological adjuvant was delivered to cancer antigen-positive lymph nodes distant from the tumor, suggesting that these lymph nodes can be targeted to improve anti-cancer immune responses. When combined with immune checkpoint blockade, delivery of immunological adjuvant to distant lymph nodes led to long-term survival and protection from recurrence. Antigen presentation by dendritic cells and T cell responses could also be recovered by exogenous delivery of IL-1β via intratumoral injection, with improved survival when combined with immune checkpoint blockade.

Conclusions: This study demonstrates that tumor-induced impairments in antigen presentation in tumor-draining lymph nodes can be overcome by the appropriate introduction of immunological adjuvant to tumor-distant lymph nodes or by restoring IL-1β to the tumor-draining lymph node. These strategies can induce high-quality, durable immune responses and have clinical implications for expanding the efficacy of immunotherapies.

Background: Chimeric antigen receptor (CAR) T-cell therapies are highly efficacious for several different hematologic cancers. However, for most CAR T targets it is observed that low surface antigen density on tumors can significantly reduce therapeutic efficacy. In this study, we explore this dynamic in the context of CD72, a surface antigen we recently found as a promising target for refractory B-cell cancers, but for which CD72 low antigen density can lead to therapeutic resistance in preclinical models.

Methods: Primary samples were accessed via institutional review board-approved protocols. Affinity-matured and humanized nanobody clones were previously described in Temple et al. (2023). CAR T cells were generated via lentiviral transduction. In vitro cytotoxicity assays were performed using luciferase-labeled cell lines. In vivo studies were performed using cell line-derived or patient-derived xenografts implanted in NOD scid gamma mice.

Results: We first confirmed ubiquitous CD72 expression across a range of primary B-cell non-Hodgkin lymphomas. We further found that after resistance to CD19-directed therapies, across both B-cell acute lymphoblastic leukemia (B-ALL) models and primary tumor samples, surface CD72 expression was largely preserved while CD22 expression was significantly diminished. Affinity maturation of a nanobody targeting CD72, when incorporated into CAR T cells, led to more effective elimination in vitro of isogenic models of CD72 low-expressing tumors. These results suggested that nanobody-based CAR T cells (nanoCARs) may exhibit a similar relationship between binder affinity, antigen expression, and efficacy as previously demonstrated only for single chain variable fragment-based CAR T cells. Surprisingly, however, this significantly improved in vitro efficacy only translated to modest in vivo survival benefit. As a parallel strategy to enhance CAR T function, we found that the small molecule bryostatin could also significantly increase CD72 surface antigen density on B-cell malignancy models. Structural modeling and biochemical analysis identified critical residues improving CD72 antigen recognition of our lead affinity-matured nanobody.

Conclusions: Together, these findings support affinity-matured CD72 nanoCARs as a potential immunotherapy product for CD19-refractory B-cell cancers. Our results also suggest that for B-ALL in particular, CD72 may be a preferable second-line immunotherapy target over CD22.

Genetic engineering has fundamentally transformed T cell-based therapies by enabling tumor targeting capability, improving their functionality, and facilitating allogeneic use. These strategies-originally developed in αβ chimeric antigen receptor (CAR)-T cells-have become increasingly established as blueprints for enhancing the function of other immune effector cells, including gamma delta (γδ) T cells. A recent study by Nishimoto et al showcased the adaptation of these engineering approaches to Vδ1 γδ T cells (ADI-270) by coexpressing a CD70-targeted CAR and a dominant-negative TGFβRII receptor (dnTGFβRII) to target CD70⁺ malignancies, addressing immunosuppression and host-versus-graft rejection. This commentary explores αβ T cell-derived engineering strategies applicable to γδ T cells, while also highlighting genome-editing innovations poised to advance next-generation γδ CAR-T development.