Oncoimmunology最新文献

Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors (TKIs) are improving the response rates of advanced renal cancer patients. However, many treated patients do not respond, making novel immune checkpoint-based immunotherapies potentially clinically beneficial only for specific groups of patients. We detected high expression of the immune checkpoint protein B7-H3 in clear cell renal cell carcinomas (ccRCCs) and evaluated B7-H3 immunohistochemistry staining in tissue microarray samples from two distinct renal cancer cohorts. B7-H3 was highly expressed in approximately 50% of primary tumors and in 30% of metastatic lesions. B7-H3 expression in primary tumors correlated with tumor necrosis, sarcomatoid transformation, disease-free survival, and synchronous metastasis, while B7-H3 expression in metastasis correlated with metastases to the lymph nodes. Gene expression analysis revealed the association of B7-H3 expression with gene expression scores involved in T cell exhaustion and myeloid immune evasion, as well as with PI3K/AKT and JAK/STAT pathways. Furthermore, knocking down B7-H3 expression in renal cancer cells by siRNA and CRISPR/Cas resulted in lower 2D and 3D cell proliferation and viability as well as increased sensitivity to TKI axitinib. Together, our findings suggest a pro-oncogenic and immune evasive role for B7-H3 in ccRCC and highlight B7-H3 as an actionable novel immune checkpoint protein in combination with TKI in advanced renal cancer.

Few clinical studies investigated the putative link between the activation of immunogenic cell death (ICD) and the oncological outcome. Recent data, published in a Phase 1b trial, demonstrated that an ICD-associated surge in the plasma concentration of high-mobility group box 1 (HMGB1) indicates favorable prognosis in patients with advanced leiomyosarcomas treated with the combination of doxorubicin, dacarbazine and nivolumab.

Apoptosis, necroptosis and pro-inflammatory NF-κB-dependent signaling are repressed by receptor-interacting serine/threonine-protein kinase 1 (RIPK1). A recent paper in Immunity describes a small molecule inducing the proteolytic degradation of RIPK1. In preclinical experiments, this RIPK1 inhibitor improved the anticancer efficacy of radiotherapy, immunotherapy (with PD-1 blockade) and radioimmunotherapy (with CTLA-4 blockade).

Hairy cell leukemia variant (HCL-v) is a rare malignancy of clonal mature B-cells that follows a chronic disease course. HCL-v patients are often resistant to purine nucleoside analogs, which are the first-line therapy. To address the shortcomings of current therapy for HCL-v, we investigated the activity of a BAFF ligand-based CAR-T cell which binds to all three BAFF receptors, BAFF-receptor, TACI, and BCMA. Here, we demonstrate that HCLv patient-derived cells highly express all three BAFF receptors and that BAFF CAR-T cells induce significant cytotoxicity in vitro against both cell lines and HCL-v patient cells. This cytotoxicity corresponds with significant CAR-T cell activation, degranulation, and release of pro-inflammatory cytokines after co-incubation with HCLv cells. Furthermore, we successfully generated BAFF CAR-T cells directly from an HCLv patient and observed direct autologous killing against patient tumor cells in vitro. These HCLv patient-derived CAR-T cells were also effective in killing the Hair-M cell line and tumor cells derived from a different HCLv patient. Lastly, we also developed two mouse xenograft models for HCL, a subcutaneous Bonna-12 model and intravenous Hair-M xenograft model. We observed decreases in tumor burden and prolonged overall survival without significant toxicity. In conclusion, here we show that BAFF CAR-T cells exert anti-tumor effects in vitro and in vivo against multiple cell lines and patient-derived HCL-v samples and may be a successful therapeutic strategy for HCLv patients.

Widespread peritoneal dissemination is common in patients with gynecologic or gastrointestinal cancers. Accumulating evidence of a central role for regional immunity in cancer control indicates that intraperitoneal immunotherapy may have treatment advantages. This study delineates immune mechanisms engaged by intraperitoneal delivery of a cell-based vaccine comprised of silicified ovarian cancer cells associated with enhanced survival. Vaccine trafficking from the site of injection to milky spots and other fat-associated lymphoid clusters was studied in syngeneic cancer models using bioluminescent and fluorescent imaging, microscopy, and flow cytometry. Spectral flow cytometry was used to phenotype peritoneal immune cell populations, while bioluminescent imaging of cancer was used to study myeloid and T cell dependency, systemic immunity, and vaccine efficacy in models of disseminated high-grade serous ovarian and DNA mismatch-repair proficient microsatellite-stable colorectal cancer. Following intraperitoneal vaccination of mice with ovarian cancer, vaccine cells were rapidly internalized by myeloid cells, with subsequent trafficking to fat-associated lymphoid clusters. Tumor clearance was confirmed to be T cell-mediated, leading to the establishment of local and systemic immunity. Combination immune checkpoint inhibitor and vaccine therapy in mice with advanced disease, characterized by an established suppressive tumor microenvironment, increased the number of mice with non-detectable tumors, however, change in tumor burden compared to vaccine monotherapy was not significant. Vaccination also resulted in tumor clearance in mouse models of metastatic colorectal cancer. This study demonstrates that intraperitoneal vaccine delivery has the potential to enhance vaccine efficacy by activating resident immune cells with the subsequent establishment of protective systemic anti-tumor immunity.

Immuno-oncological cancer management is shifting to neoadjuvant treatments. In patients with gastrointestinal cancers, particularly locally advanced rectal cancer, neoadjuvant chemoimmunotherapy often induce complete responses, hence avoiding surgical intervention. Recent clinical trials indicate that combinations of oxaliplatin-based chemotherapy and PD-1/PD-L1-targeting immunotherapy can be safely administered before surgery with curative intent.

Dendritic cells (DCs) are critical players at the intersection of innate and adaptive immunity, making them ideal candidates for anticancer vaccine development. DC-based immunotherapies typically involve isolating patient-derived DCs, pulsing them with tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs), and utilizing maturation cocktails to ensure their effective activation. These matured DCs are then reinfused to elicit tumor-specific T-cell responses. While this approach has demonstrated the ability to generate potent immune responses, its clinical efficacy has been limited due to the immunosuppressive tumor microenvironment. Recent efforts have focused on enhancing the immunogenicity of DC-based vaccines, particularly through combination therapies with T cell-targeting immunotherapies. This Trial Watch summarizes recent advances in DC-based cancer treatments, including the development of new preclinical and clinical strategies, and discusses the future potential of DC-based vaccines in the evolving landscape of immuno-oncology.

Follicular lymphoma (FL), the second most common subtype of non-Hodgkin lymphoma, relies on interactions with immune elements in the tumor microenvironment, including T-follicular helper cells and follicular dendritic cells, for its survival and progression. Despite its initial responsiveness to chemoimmunotherapy, FL is generally considered incurable. Strategies to improve immune-mediated control of FL could significantly benefit this population, particularly as it includes many elderly and comorbid patients. Immune cell engagers, especially bispecific antibodies (BsAbs), are crucial in targeting FL by bridging tumor and effector cells, thereby triggering T-cell activation and cytotoxic killing. CD3 × CD20 BsAbs have shown the most promise in clinical development for B-NHL patients, with structural variations affecting their target affinity and potency. This review summarizes the current clinical trials of BsAbs for relapsed/refractory FL, highlighting the approval of some agents, their role in first-line treatment or combination therapies, their toxicity profiles, and the future of this therapeutic approach compared to other immune cell therapies.

Acyl CoA binding protein (ACBP, which is encoded by diazepam binding inhibitor, DBI) acts on the gamma-amino butyric acid (GABA) receptor type A via a specific binding site that is shared by diazepam and other benzodiazepines. Both ACBP/DBI and benzodiazepines act as positive allosteric modulators, hence increasing GABA effects on this receptor. Recently, we found that ACBP/DBI acts as an endogenous immunosuppressor, meaning that its antibody-mediated neutralization has immunostimulatory effects and enhances the efficacy of immunotherapy and chemoimmunotherapy in mouse models. Driven by these considerations, we investigated whether diazepam administration in mice would reverse the beneficial effects of ACBP/DBI neutralization on cancer chemoimmunotherapy. Indeed, diazepam abolished the therapeutic of anti-ACBP/DBI antibodies, supporting the idea that diazepam exerts immunosuppressive properties. Of note, treatment with benzodiazepines was associated with poor clinical responses to chemoimmunotherapy in patients with non-small cell lung cancer (NSCLC) as compared to individuals not receiving any psychotropic drugs. Medication with other psychotropic drugs than benzodiazepines did not compromise the outcome of chemoimmunotherapy, indicating that this immunosuppressive effect was benzodiazepine specific. We conclude that benzodiazepines may confer systemic immunosuppression. This hypothesis requires further epidemiological and clinical confirmation.

Acyl CoA binding protein (ACBP) encoded by DBI is a tissue hormone that limits autophagy in multiple cell types, hence acting as an extracellular autophagy checkpoint. We recently reported in Molecular Cancer that monoclonal antibodies neutralizing ACBP improve immunosurveillance of breast and lung carcinomas. Moreover, ACBP neutralization improves the outcome of neoadjuvant chemoimmunotherapy with PD-1 blockade in preclinical models.