Journal for Immunotherapy of Cancer最新文献

Neoadjuvant chemoimmunotherapy (chemo-IO) has fundamentally reshaped the treatment paradigm for resectable non-small cell lung cancer (NSCLC), challenging long-held surgical boundaries and redefining what constitutes "resectable" disease. Trials such as CheckMate-816, KEYNOTE-671, and AEGEAN have demonstrated that integrating immune checkpoint blockade with chemotherapy yields unprecedented rates of pathological response and event-free survival, positioning chemo-IO as the new global standard for stage IB-IIIA NSCLC. Yet these advances bring new complexities; how do we define resectability in an era of immunotherapeutic downstaging, and how should multidisciplinary teams adapt to evolving biology? Traditional radiological and anatomic criteria now sit alongside immune-mediated regression and circulating tumor DNA (ctDNA) kinetics as measures of treatment success. ctDNA clearance and pathological response serve as powerful surrogates for long-term survival, with ongoing studies such as MERMAID-1/2 exploring their potential to guide adjuvant therapy and spare overtreatment. The modern challenge lies in integrating these biomarkers into surgical decision-making and developing standardized, biology-informed resectability frameworks. Future progress will depend on close collaboration between surgeons, oncologists, and translational scientists to expand surgical candidacy safely and define the next generation of curative strategies in lung cancer.

Background: The CDKN2A gene encodes two canonical tumor suppressors, p16INK4A and p14ARF, which safeguard cells from malignant transformation by inducing cell cycle arrest and apoptosis in response to aberrant growth signals. Paradoxically, many cancers overexpress these proteins when downstream effectors that enforce negative feedback regulation are lost or inactivated. For example, p14ARF, which regulates p53 activation, is aberrantly expressed in more than 50% of tumors with inactivating p53 mutations. Here, we evaluated the feasibility of targeting dysregulated p16INK4A and p14ARF expression using TCR-T cell therapeutics.

Methods: We analyzed a panel of p16INK4A- and p14ARF-derived peptides for HLA-A*02:01-associated presentation and recognition by CD8⁺ T cells. Antigen-specific T cell receptors were isolated from healthy donor repertoires and expressed in primary T cells to assess specificity, functional avidity, tumor recognition, and safety using in vitro T cell functional assays, in vivo tumor models, and an in vivo safety model.

Results: We identified a unique and well-presented p14ARF epitope that was consistently detected in the HLA-A*02:01-associated immunopeptidome of cancer biopsies but not in normal tissues. High-avidity ARF-specific TCRs were isolated from the peripheral repertoire of healthy donors, and TCR-transduced T cells mediated potent tumor cell killing in vitro and in vivo in preclinical models. Furthermore, targeting p14ARF-expressing cells did not result in detectable on-target toxicity in an in vivo safety model.

Conclusions: These findings demonstrate the feasibility of targeting dysregulated tumor suppressor proteins with TCR-T cell therapeutics and identify p14ARF as a promising target for future therapies.

Background: Immunotherapy has had limited success in pancreatic cancer, largely due to a low mutational burden and immunosuppressive microenvironment. Here we hypothesized that systemic delivery of viral antigens can redirect pre-existing antiviral immunity against pancreatic tumors.

Methods: Cytomegalovirus (CMV, a β-herpesvirus) was chosen, as the majority of the population is infected and it induces an extremely large/broad memory T-cell response. Mice latently infected with murine CMV (MCMV) were orthotopically implanted with pancreatic cancer cells and treated with systemic injections of MCMV T-cell epitopes. Tumor growth was monitored by ultrasound two times a week, and immune cell infiltration was analyzed by histology, flow cytometry and single-cell RNA sequencing (scRNA-seq). Statistical analysis was performed by two-way analysis of variance with Sidak correction.

Results: MCMV peptide-epitope therapy (MCMVp) promoted preferential accumulation of MCMV-specific T cells within pancreatic tumors, delaying tumor growth and increasing survival. Immunophenotyping and scRNA-seq analyses showed these T cells were highly activated and cytotoxic, leading to increased tumor necrosis and caspase-3 activation. Depletion of CD4 and CD8 T cells abolished the impact of MCMVp therapy, indicating the antitumor response is T-cell dependent. Together, these results show that CMV-specific T cells can be repurposed to combat pancreatic cancer.

Conclusions: Our studies reveal that CMV-specific viral memory T cells can be re-directed to control a solid tumor normally refractory to immunotherapy via a simple, intravenous injection of T-cell peptide epitopes. This mutation-agnostic approach has significant potential for the development of "off-the-shelf" therapeutics by stimulating pre-existing antiviral memory, and it is widely applicable due to the high prevalence of CMV.

Background: The rapidly advancing field of cancer therapy has sparked growing interest in the potential synergy between anticoagulation and immune checkpoint inhibitor (ICI) therapy. Recent research highlights that anticoagulants, traditionally used for thromboprophylaxis and managing thromboembolic events, may also exhibit immunomodulatory properties. These properties can influence the tumor microenvironment by promoting immune cell infiltration, enhancing antitumor immune responses, and potentially reducing metastasis. This emerging evidence underscores the complex interplay between coagulation pathways and immune regulation, paving the way for further exploration of the clinical benefits of combining anticoagulation with ICI therapy.

Methods: A systematic review was conducted to synthesize the current evidence on the interplay between anticoagulation and ICI. Relevant studies examining their mechanisms of action, clinical outcomes, and potential interactions were identified and analyzed. Comprehensive database searches were performed to ensure a thorough and inclusive review of the literature.

Results: Preclinical studies consistently show that combining ICIs with anticoagulants can enhance cancer treatment by inhibiting tumor growth and metastasis. In particular, low molecular weight heparin, oral factor Xa (FXa) inhibitors, and platelet inhibitors have demonstrated synergistic effects with ICI. However, these findings have not been consistently replicated in clinical settings. While two retrospective studies reported no significant impact of anticoagulants on ICI efficacy, one retrospective study found improved outcomes in advanced melanoma patients treated with ICI and FXa inhibitors. Additionally, another retrospective study revealed a significant association between platelet aggregation inhibition and extended progression-free survival.

Conclusions: Our literature review underscores the intricate relationship between anticoagulation and ICIs in cancer therapy. Future studies should prioritize exploring the interactions between ICI, FXa inhibitors, and antiplatelet agents.

Background: Acquired resistance to KRAS G12C inhibitor sotorasib remains a critical challenge in non-small cell lung cancer treatment. A deeper, rational understanding of resistance mechanisms can enable the development of therapeutic strategies to overcome resistance.

Methods: We established a syngeneic resistant model after prolonged AMG-510 treatment in C57BL/6 mice. In addition, the in vitro co-culture model and multiple methods including flow cytometry and western blot were used to assess the changes of immune microenvironment during resistance. Finally, a serial combinatorial therapy strategy was applied in the resistant mouse model to evaluate its ability to reverse resistance.

Results: Upregulation of PD-L1 in KRAS G12C tumors drives an immunosuppressive tumor microenvironment and promotes acquired resistance characterized by reduced infiltration of cytotoxic CD8⁺ T cells and a marked expansion of myeloid-derived suppressor cells through JAK2/STAT3/IL-6 Pathway. These mechanisms promote tumor immune evasion and protection from cell apoptosis, thereby establishing a microenvironment that sustains acquired resistance to sotorasib. Critically, sequential administration of a PD-L1 inhibitor (PD-L1i) effectively reprogrammed the immunosuppressive microenvironment, restoring antitumor immunity and re-sensitizing resistant tumors to sotorasib treatment.

Conclusions: These results identify the PD-L1-driven immunosuppressive microenvironment as a key mediator of sotorasib resistance and propose PD-L1i as a synergistic strategy to overcome resistance, which warrants clinical exploration of sequential or combinatorial regimens.

Background: Crosstalk between inflammation and the immune system plays an important role in tumor malignant progression, immune evasion, and immunotherapy efficacy. This study aims to explore the significance of inflammation-associated gene ribosomal-binding protein 1 (RRBP1) in modulating tumor malignant progression and immune escape.

Methods: This study was used transcriptome, proteomic and in vivo anti-programmed death-ligand 1 (PD-L1) antibody CRISPR Cas9 screening data to identify RRBP1 as an inflammation-immune-associated gene in bladder cancer (BC). Immunohistochemistry, single-cell RNA sequencing, multiplex immunofluorescence, flow cytometry, RNA sequencing, and animal experiments were used to study the role of RRBP1 in regulating tumor malignant progression and immunotherapy efficacy.

Results: RRBP1 overexpression promoted the proliferation and metastasis of BC both in vitro and in vivo. RNA sequencing and single-cell RNA sequencing revealed that RRBP1 inhibition activated immune-associated pathways and reshaped the tumor immune microenvironment by altering the infiltration of CD8⁺ T-cell subpopulations, thereby enhancing antitumor immunity. Mechanistically, RRBP1 inhibition enhances the secretion of CXCL10 by cancer cells, which binds to CXCR3 on CD8⁺ T cells to promote interferon-γ and Granzyme B expression. Furthermore, genetic and pharmacological inhibition of RRBP1 sensitizes tumors to anti-PD-L1 therapy.

Conclusions: Our findings highlight RRBP1 as an inflammation-immune-associated gene that inhibits tumor progression and improves immunotherapy efficacy by regulating the CXCL10-CXCR3 axis in the tumor microenvironment.

Background: Current immunotherapy regimens most often fail due to an insufficient T cell response and/or immune-related adverse events (irAEs) which lead to treatment discontinuation. Additionally, many cancers likely require combination immunotherapies which may further increase irAE. This is exemplified in our preclinical models of dual targeting of regulatory T cells with a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor and antibodies to LAG-3. Indeed, while this approach in preclinical models of triple-negative breast cancer shows excellent tumor control, treatment is poorly tolerated and results in significant toxicity. Given the emerging relevance of these targets in human breast cancer, we explored strategies to sustain tumor immunity while mitigating toxicity using these therapeutic modalities.

Methods: Different approaches to combination immunotherapies employing a PI3Kδ inhibitor (PI-3065) with LAG-3 targeting treatments were tested in a mouse model of triple-negative breast cancer to optimize tumor control while limiting irAE.

Results: Systemic targeting of the LAG-3 ligand FGL1 did not provide additional anticancer benefit but markedly worsened irAE. Localized delivery of anti-LAG-3 antibodies to the tumor microenvironment promoted tumor control while reducing the overall number of animals experiencing severe irAE compared with those receiving systemic LAG-3 blockade. However, intermittent dosing of the PI3Kδ inhibitor in combination with anti-LAG-3 treatment prevented the initial development of irAE and enabled excellent tumor control without systemic adverse effects.

Conclusions: Our data demonstrated that refining immunotherapy delivery approaches can improve tolerability that ultimately transforms treatment success.

Background: The high mortality rate of patients with colorectal cancer combined with the lack of nontoxic and efficient personalized treatments makes it urgent to develop new targeted therapies for this disease. B7-H3 appears to be a good target, as it is overexpressed in tumor tissue compared with normal tissue. However, B7-H3 is a molecule with ambivalent functions and is expressed by different cell types. This complexity has contributed to the delay in identifying cell subtypes that express B7-H3 and their potential role in colorectal oncogenesis.

Methods: In this integrated multiomics study, we used in silico bulk, single-cell, and spatial transcriptomic data to investigate the clinical and biological characteristics of tumors with high B7-H3 expression, the specific cell types expressing high levels of B7-H3, and their temporal appearance during colorectal oncogenesis.

Results: We found that tumors with high B7-H3 expression corresponded to tumors with a predominant stroma composed mainly of fibroblasts. Among them, two subtypes of extracellular matrix-related myofibroblastic cancer-associated fibroblasts and profibrotic pericytes specifically expressed high levels of B7-H3, the former being an independent factor for poor prognosis in patients with colorectal cancer. Finally, by examining precancerous lesions, we report that fibroblast subtypes with high levels of B7-H3 appear early during oncogenesis, especially at the inflamed stage.

Conclusions: We suggest that anti-B7-H3 immunotherapies might preferentially target cells from the microenvironment rather than tumor cells. This is particularly important for understanding the mode of action of the anti-B7-H3 antibody‒drug conjugate, which is currently being tested in clinical trials in several solid tumors.

Background: Prostate cancer (PCa) is a prevalent malignancy with limited treatment options for advanced stages. Oncolytic virotherapy represents a promising immunotherapeutic approach, but its efficacy and underlying mechanisms in PCa, particularly concerning immune checkpoint regulation, remain unclear.

Methods: The antitumor effects of the oncolytic virus oncolytic herpes simplex virus type 2 (OH2) were evaluated in PCa cell lines and mouse models. Transcriptome sequencing, western blot, chromatin immunoprecipitation-sequencing-quantitative PCR, and flow cytometry were employed to investigate the mechanism of programmed death 1 ligand 1 (PD-L1) regulation. A targeted delivery system, reactive oxygen species (ROS)-responsive aptamer-conjugated anti-prostate-specific membrane antigen (PSMA) extracellular vesicles (RRA-AP-EVs), was engineered from anti-PSMA single chain variable fragment (scFv)-modified extracellular vesicles and an ROS-responsive PD-L1 blocking aptamer. OH2 was loaded via membrane extrusion, and the resulting OH2@RRA-AP-EVs were tested for targeting and therapeutic efficacy following intravenous administration.

Results: OH2 effectively killed PCa cells but simultaneously activated the IKK/I-κBα/p65 pathway, leading to PD-L1 upregulation and adaptive immune resistance. While combining OH2 with anti-PD-L1 improved outcomes, clinical translation was hindered by delivery challenges. The novel OH2@RRA-AP-EVs system demonstrated precise tumor targeting and ROS-triggered local PD-L1 blockade. Intravenous injection of OH2@RRA-AP-EVs showed superior tumor control (inhibiting tumor growth by 70% vs free OH2) and enhanced CD8+T cell infiltration and function compared with free OH2 (greater than twofold increase in intratumoral CD8+T cell infiltration along with over twofold upregulation of key effector molecules).

Conclusion: This study identifies a mechanism of OH2-induced PD-L1 expression in PCa and provides a versatile, targeted delivery platform that enables effective intravenous viro-immunotherapy, overcoming key translational barriers.