Journal for Immunotherapy of Cancer最新文献

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.

Background: Patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) often respond to cytotoxic therapy, but early disease progression is typical. Responses to immunotherapy alone are rare. Recent advances in chemoimmunotherapy combinations offer promise. We report results from cohorts A and B of REVOLUTION, an adaptive platform trial designed to evaluate the safety and antitumor activity of chemoimmunotherapy combinations in untreated mPDAC.

Methods: REVOLUTION (NCT04787991) is an open-label, exploratory platform trial. Patients were assigned to enrolling cohorts in a non-randomized fashion. All patients received gemcitabine (1,000 mg/m²), nab-paclitaxel (125 mg/m²), and two doses of ipilimumab (1 mg/kg), administered intravenously. In addition, cohort A received nivolumab (360 mg intravenously every 3 weeks) and cohort B received hydroxychloroquine (600 mg orally two times a day). The primary endpoint was safety. Secondary endpoints included objective response rate (ORR), disease control rate, duration of response, progression-free survival, and overall survival (OS). Exploratory endpoints included pharmacodynamic changes and associations between biomarkers and clinical outcomes.

Results: Both cohorts enrolled 15 patients. Grade 3-4 treatment-related adverse events occurred in 60% and 53% of patients in cohorts A and B, respectively. One grade 5 event occurred in cohort B, which exhibited more frequent dose modifications and non-compliance. Cohort A demonstrated an ORR of 33% (5/15) and a 12-month OS rate of 65.5% (95% CI 35.7% to 84.0%), with higher baseline levels of programmed cell death protein-1 (PD-1)⁺CD39⁺ central memory CD4⁺ T cells associated with prolonged survival. Cohort B demonstrated an ORR of 40% (6/15) and a 12-month OS rate of 53.9% (95% CI 24.3% to 76.3%). Cohort A showed increases in activated and proliferating CD4⁺ and CD8⁺ T cells, regulatory T cells, and circulating soluble PD-1 and Th1-associated cytokines. Cohort B exhibited delayed but sustained increases in activated CD4⁺ T cells and pharmacodynamic evidence of autophagy inhibition.

Conclusions: REVOLUTION cohorts A and B demonstrated encouraging antitumor activity in patients with mPDAC. In cohort B, hydroxychloroquine-related tolerability issues contributed to early discontinuations and reduced drug exposure. These findings highlight the potential and limitations of current chemoimmunotherapy approaches. Although neither cohort will be expanded, the results reinforce the continued promise of chemoimmunotherapy in mPDAC and the importance of refining these strategies.

Background: Neoadjuvant PD-1/PD-L1 blockade yields robust efficacy in advanced cutaneous squamous cell carcinoma (cSCC), yet many patients fail to achieve a complete or major pathologic response. The reasons why some patients experience response but others do not are unclear.

Methods: We profiled cSCC specimens before, after 1 dose, and after 3-4 doses of PD-1/PD-L1 blockade to uncover resistance mechanisms and predict therapeutic response. In total, 27 patients across three cohorts, including two phase II trials, were studied. We created 1.7 mm tissue-core microarrays and performed single-cell spatial transcriptomics, including spatial clustering, gene-set enrichment, and spatial correlation analyses.

Results: After profiling all samples, six distinct spatial niches emerged, each differentially enriched in responders versus non-responders. A high antigen presentation niche, B/plasma cell enriched niche, and inflammatory keratinocyte niche were more frequent in responders, whereas proliferative keratinocyte, low antigen presentation myeloid, and fibroblast-rich epithelial-mesenchymal transition niches prevailed in non-responders. Notably, spatial niche profiling on pretreatment samples outperformed PD-L1 status in predicting pathologic response. Each niche displayed unique gene coexpression modules, suggesting niche-specific resistance mechanisms. Individual tumor analyses revealed varied immune evasion strategies, including defective interferon-induced antigen presentation, immunosuppressive myeloid environments, and epithelial-mesenchymal transition.

Conclusions: Our single-cell spatial transcriptomic approach identifies six spatial niches that predict immunotherapy response better than PD-L1 status using only 1.7 mm tissue cores and may inform the development of biomarkers. Our results further underscore the heterogeneity of resistance mechanisms among cSCC patients, highlighting the need for tailored therapeutic strategies.

Background: Although immunotherapy has revolutionized cancer treatment, its efficacy in castration-resistant prostate cancer (CRPC) remains limited, largely due to an immunologically "cold" tumor microenvironment with scarce T-cell infiltration. Unraveling the molecular mechanisms underlying immune evasion and developing novel strategies to activate innate antitumor immunity are therefore critical to overcoming immunotherapy resistance in CRPC.

Methods: Using bioinformatic approaches, we analyzed the protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) expression and its correlation with immune cell infiltration and response to immune checkpoint blockade (ICB) in public databases. PKMYT1 protein expression was further evaluated via immunohistochemistry in a clinical cohort of prostate cancer (PCa) specimens. Mechanistic investigations were conducted in PCa cell lines and mouse models. The immunological impact of PKMYT1 inhibition was delineated using single-cell RNA sequencing, and the therapeutic efficacy of RP-6306, either as monotherapy or in combination with programmed death-ligand 1 (PD-L1) blockade, was evaluated in syngeneic mouse models.

Results: PKMYT1 expression was significantly overexpressed in CRPC compared with primary PCa. High PKMYT1 expression correlated with a suppressed antitumor immunity and poor clinical response to ICB. Mechanistically, PKMYT1 inhibition activated the cyclic guanosine monophosphate-adenosine monophosphate adenosine synthase (cGAS)-stimulator of interferon genes (STING) pathway, potentiated both type I and II interferon signaling, and upregulated chemokines, including CCL5 and CXCL10. The selective PKMYT1 inhibitor, RP-6306, enhanced the efficacy of ICB in the presence of CD8⁺ T cells. Treatment with a PKMYT1 inhibitor alone or in combination with PD-L1 blockade significantly increased the infiltration of activated CD8⁺ T cells and induced significant tumor suppression in vivo.

Conclusion: PKMYT1 is a pivotal dual regulator of tumor progression and immune evasion in CRPC. Our findings provide a compelling preclinical rationale for targeting PKMYT1 as a novel strategy to reprogram the tumor immune microenvironment and overcome resistance to immunotherapy.