Oncoimmunology最新文献

Medulloblastoma (MB) is a pediatric brain tumor that develops in the cerebellum, representing one of the most common malignant brain cancers in children. Standard treatments include surgery, chemotherapy, and radiation, but despite a 5-y survival rate of approximately 70%, these therapies often lead to significant neurological damage in the developing brain. This underscores the urgent need for less toxic, more effective therapeutic alternatives. Recent advancements in cancer immunotherapy, including immune checkpoint inhibitors and CAR-T cell therapy, have revolutionized cancer treatment. One promising avenue is the use of Gamma Delta (γδ)T cells, a unique T cell population with potential advantages, such as non-alloreactivity, potent tumor cell lysis, and broad antigen recognition. However, their capacity to recognize and target MB cells remains underexplored. To investigate the therapeutic potential of γδT cells against MB, we analyzed the proportion and status of MB-infiltrated γδT cells within patient datasets. We next investigated the expression of γδT cell ligands on MB cells and identified the EphA2 receptor and the phosphoantigen/Butyrophilin complex as key ligands, activating Vγ9 Vδ1 and Vγ9 Vδ2 T cells, respectively, leading to significant MB cell lysis in both monolayer and spheroid models. Importantly, preliminary safety data showed that γδT cells did not target differentiated neurons or neuroepithelial stem cells derived from induced pluripotent stem cells, underscoring the selectivity and safety of this approach. In conclusion, γδT cells trigger an efficient and specific killing of MB and would offer a promising novel therapeutic strategy.

Renal cell carcinoma (RCC) is recognized as an immunogenic tumor, yet tumor-infiltrating lymphocytes often exhibit diminished effector function. However, the mechanisms underlying reduced T and NK cell activity in RCC remain unclear. Here, we examined the immune contexture in RCC patients undergoing nephrectomy to identify immune-related biomarkers associated with disease progression. Immune cell phenotypes and secretion profiles were assessed using flow cytometry and Luminex multiplex analysis. Supervised multivariate analysis revealed several changes of which frequencies of T and NK cells expressing CCR5, CXCR3, and PD-1 were elevated within tumors compared with peripheral blood. In addition, higher levels of regulatory T cells, PD-1+, and CXCR3+ T and NK cells were observed in patients with relapse following nephrectomy. With regards to soluble factors, tumor-derived CXCL8 was associated with higher Fuhrman grade and increased frequency of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). These biomarkers demonstrate potential relevance in the progression of RCC and merit further investigation in prospective studies.

The search for reliable shared tumor-specific antigens (TSAs) to improve cancer immunotherapy is on-going. The so-called non-coding regions of the genome have recently been shown to give rise to immunogenic peptides, including the melanoma-specific antigen MELOE-1 which is translated from the long intergenic non-coding RNA (lincRNA) meloe in an IRES-dependent manner. Here, we present a strategy to systematically identify tumor-specific antigens produced by ORFs within lincRNAs with IRES-like upstream structures. We provide evidence suggesting that in the melanocytic lineage a significant proportion of the selected lincRNAs can produce immunogenic peptides. T cell repertoires against some of these peptides were found in peripheral blood mononuclear cells (PBMCs) from healthy donors and melanoma patients, and in tumor-infiltrating lymphocytes (TILs) from metastatic melanoma patients. Finally, CD8+ T cell lines from melanoma patients specific for three of the characterized HLA-A *0201 epitopes could recognize melanoma cell lines, which were enhanced by reticular stress. Thus, these peptides may represent a new class of shared TSAs in melanoma and are attractive candidates for evaluation as targets for immunotherapy in preclinical studies. In addition, our selection strategy has the potential to identify new lincRNA-derived antigens in other cancers.

The immune landscape of healthy prostate and its alterations during prostate cancer (PCa) progression remain poorly characterized. Using scRNA-sequencing and multiparametric flow-cytometry analysis, we comprehensively characterized immune cells in wild-type and PTEN^(i)pe-/- mouse prostates, a model that closely recapitulates human PCa. PCa in PTEN^(i)pe-/- is marked by the recruitment of tumor-associated neutrophils (TANs), which represent the dominant immune cell population and resolved into eight distinct states, Trem2⁺ tumor-associated-macrophages (TAMs), and exhausted CD8⁺ T cells. Trem2⁺ TAMs differ from the three main resident macrophage populations in the healthy prostate, exhibiting a strong metabolic and immunosuppressive signature, likely driven by the MIF/HIF1A-signaling axis. This study provides the first detailed characterization of immune cells in the healthy mouse prostate and reveals changes in the immune landscape associated with prostate cancer progression.

Among the plethora of cancer immune evasion mechanisms, T-cell-inhibiting factors within the tumor microenvironment impose a major challenge for the development of novel immunotherapies. Strategies to overcome immunosuppression and remodel the TME are therefore urgently needed. Therapeutic cancer vaccines based on engineered arenaviruses have been proven to generate potent tumor specific CD8+ T-cell responses in preclinical models and cancer patients. Despite signs of clinical activity as monotherapy, combination therapies are needed to further increase the therapeutic effect. To address this need, we evaluated the efficacy of recombinant vectors based on lymphocytic choriomeningitis virus encoding the T-cell stimulating cytokines IL-7, IL-12 and IL-15 with or without tumor-associated antigens. These vectors were tested in three different mouse tumor models (TC-1, MC-38 and B16.F10). Our results demonstrate that only IL-12 encoding vectors led to increased immunogenicity and efficacy, which, after systemic administration, was associated with adverse events. The safest and most potent regimen consisted of systemic vaccination with tumor antigen encoding vectors and local injection of IL-12-encoding vectors. A single round of this treatment regimen resulted in 86-100% tumor-free mice and warrants further investigation.

Sertraline and indatraline are two antidepressants that function as serotonin reuptake inhibitors and have demonstrated promising anticancer potential, although their precise mechanisms of action remain unclear. Both compounds trigger cholesterol accumulation within lysosomes followed by lysosomal membrane permeabilization, ultimately leading to the activation of immunogenic cell death (ICD). This, in turn, triggers a T cell-mediated adaptive immune response that facilitates significant tumor control.

BCMA-directed CAR-T therapies have shown promising results in multiple myeloma (MM). However, patients continue to relapse. T cell exhaustion with increased TIGIT expression is a resistance mechanism which was confirmed in CAR-T cells from ARI0002h trial, an academic CAR-T developed in our institution. We aimed to analyze the impact of blocking TIGIT on the efficacy of ARI0002h. We used three different strategies to block TIGIT: (1) Addition of an external blocking anti-TIGIT-antibody (Ab), (2) Modify ARI0002h into a 4^th generation CAR-T, named ARITIGIT, capable of secreting a soluble TIGIT-blocking scFv and (3) TIGIT knock-out in ARI0002h using CRISPR/Cas9. Each strategy was evaluated in vitro and in vivo. Adding a TIGIT-blocking Ab to ARI0002h improved in vitro cytotoxicity, but failed to enhance mice survival. The new 4^th generation CAR-T, ARITIGIT, was also unable to achieve better survival outcomes despite favoring the in vivo model by using a myeloma cell line with high expression of the TIGIT ligand PVR. Interestingly, when mice were challenged with a second infusion of tumor cells, mimicking a relapse model, a trend for improved survival with ARITIGIT was observed (p = 0.11). Finally, TIGIT-knock-out on ARI0002h (KO-ARI0002h) using CRISPR/Cas9 showed similar in vitro activity to ARI0002h. In an in vivo stress model, TIGIT KO-ARI0002h prolonged survival (p = 0.02). However, this improvement was not significant compared to ARI0002h (p = 0.07). This study failed to demonstrate a significant benefit of TIGIT-blockade on ARI0002h cells despite using three different approaches, suggesting that targeting a single immune checkpoint may be insufficient.

The annual ImmunoRad Conference has established itself as a recurrent occasion to explore the possibility of combining radiation therapy (RT) and immunotherapy (IT) for clinical cancer management. Bringing together a number of preclinical and clinical leaders in the fields of radiation oncology, immuno-oncology and IT, this annual event fosters indeed essential conversations and fruitful exchanges on how to address existing challenges to expand the therapeutic value of RT-IT combinations. The 8th edition of the ImmunoRad Conference, which has been held in October 2024 at the Weill Cornell Medical College of New York City, highlighted exciting preclinical and clinical advances at the interface between RT and IT, setting the stage for extra progress toward extended benefits for patients with an increasing variety of tumor types. Here, we critically summarize the lines of investigation that have been discussed at the occasion of the 8th Annual ImmunoRad Conference.

Antibody-drug conjugates (ADCs) enable targeted delivery of cytotoxic payload to cancer cells. Here, we characterized the mode of action of the ADC patritumab deruxtecan, which is a monoclonal antibody specific for Erb-B2 Receptor Tyrosine Kinase 3 (ERBB3, best known as HER3) coupled to the topoisomerase-I inhibitor DXd. Patritumab deruxtecan decreased viability and induced the relocation of calreticulin fused to green fluorescent protein (CALR-GFP) to the periphery of human osteosarcoma U2OS cells engineered to express HER3 but not in their parental counterparts only expressing the CALR-GFP biosensor. Patritumab deruxtecan as well as its payload DXd induced various traits of immunogenic cell death (ICD) including antibody detectable calreticulin membrane exposure, exodus of high mobility group protein B1 (HMGB1), as well as the release of ATP into cell culture supernatants. Moreover, DXd causes rapid inhibition of DNA-to-RNA transcription, which is a key predictor for ICD. Mouse cancer cells treated with DXd were able to vaccinate syngeneic immunocompetent mice against tumor challenge. Tumor-free mice developed immune memory that led to the rejection of syngeneic tumors after rechallenge. In conclusion, patritumab deruxtecan is equipped with a cytotoxic payload that induces hallmarks of ICD in vitro and elicits antitumor immunity in vivo.

Adoptive cell therapy and the use of monoclonal antibodies are two therapeutic modalities implemented in the treatment of multiple myeloma (MM). In this study, we combined the anti-CD38 therapeutic mAb daratumumab with different types of NK cells, leveraging the antibody-dependent cell-mediated cytotoxicity (ADCC) performed by these immune cells. Daratumumab was initially combined with activated and expanded NK cells (eNK), resulting in significant cytotoxic activity against human MM cell lines. As an alternative model to minimize the variability among donors of NK cells, the NK92 cell line was used, which showed greater cytotoxic activity than eNK cells against MM cell lines. However, since NK92 cells lacked CD16 receptor expression, they could not be used in combination with mAbs. To circumvent this, we performed a CD16 transfection on NK92 cells, generating the stable NK92-CD16 cell line. These cells were tested in combination with daratumumab against human MM cell lines with excellent results under various conditions, such as 2D and 3D cultures, even at very low effector-to-target ratios. NK92-CD16 cells were then tested in the presence of daratumumab against plasma cells from MM patients, with anti-myeloma activity even against cells from relapsed patients. In vivo experiments using MM xenografts or intravenous injection of MM cells in NGS mice, followed by treatment with NK92-CD16 cells in the presence or absence of daratumumab showed tumor regressions, especially in the second model, with nearly complete elimination of the MM cells when NK92-CD16 cells were combined with daratumumab.