Oncoimmunology最新文献

Bacille Calmette-Guerin (BCG) is the immunotherapy of choice for high-risk non-muscle invasive bladder cancer (BC), although recurrence eventually occurs in 50% of patients and 20% progress to advanced stages. This study evaluates the predictive value of human leukocyte antigen class-I (HLA-I) genotyping to guide BCG immunotherapy. HLA-I genotyping and expression of NK cell receptors in circulating T and NK lymphocytes was evaluated at diagnosis in 325 consecutive BC patients (151 treated with BCG and 174 with other therapies), 648 patients with other cancers and 23,250 healthy controls. Proliferation, cytotoxicity, and production of cytokines and intracellular nitric oxide (icNO) was assessed in peripheral blood mononuclear cells from these donors, selected based on their Bw4 genotype, after stimulation in vitro with anti-CD3/CD28 or BCG. HLA-A*11, HLA-B*07 and HLA-B*18 allotypes were associated with favorable outcomes after BCG therapy (longer progression-free and overall survival), whereas HLA-B*44 and other KIR3DL1 Bw4 ligands were associated with unfavorable outcomes. Although Bw4 ligands were associated with better NK cell education in vivo (CD226-upregulation, KIR3DL1 downregulation and stronger NK cytotoxic capacity), they were also associated with weaker NK cell proliferation, and lower IL-1β, IL-6, and icNO production after BCG stimulation in vitro, revealing an inhibitory role of KIR3DL1. Mechanisms by which KIR3DL1/Bw4 interaction interferes with BCG-induced NK cell proliferation and the production of cytokines and icNO, warrant further investigation. HLA-I genotyping should be investigated as a useful biomarker to personalize BCG immunotherapy in BC.

Dendritic cells (DCs) are central players in the immune system, serving as a bridge between innate and adaptive immunity. Their unique abilities to capture, process, migrate, and present tumor-associated antigens to T cells make them essential actors in initiating and regulating anti-tumor immune responses. This review provides an overview of the phenotypic heterogeneity and functional diversity of DC in cancer immunity, with an emphasis on their interactions with other immune cells within the tumor microenvironment, highlighting their collaborative efforts in driving effective antitumor immunity. Additionally, we examined the impact of tumor-derived signals and immunosuppressive mechanisms on DC functions and their implications for DC-based cancer immunotherapy.

In a recent paper published in Cell, Li et al. suggest that selective serotonin reuptake inhibitors (SSRIs) antidepressants act on serotonin transporters on CD8⁺ T cells to enhance antitumor immunity. Beyond this mechanism, SSRIs can act on malignant cells, as well as on other immune cells, to improve cancer immunosurveillance.

Immune checkpoint blockade (ICB) has revolutionized the treatment of advanced malignancies such as melanoma. However, a significant proportion of patients fail to respond, owing to mechanisms that remain poorly understood. Here, we developed murine melanoma cell lines (R1 and R2) derived from MO4 tumors and that are resistant to anti-PD-1 therapy. These resistant cells exhibited increased tumor initiation capacity in vivo correlating with enhanced spheroid formation in vitro, and greater invasiveness and metastatic potential in a lung macrometastasis model. Mechanistically, both R1- and R2- derived tumors showed enrichment of a cancer stem cell (CSC)-like population overexpressing Wnt3a, which correlated with reduced infiltration and impaired function of CD8⁺ tissue-resident memory (TRMs) T cells. This suggested a functional link between Wnt-driven cancer stemness and TRMs dysfunction. Pharmacological inhibition of Wnt/β-catenin signaling in vitro enhanced CD8⁺ T cell proliferation and expression of functional markers. Notably, Wnt/β-catenin inhibition in vivo reversed anti-PD-1 resistance in resistant tumors, coinciding with reduced OCT4⁺Wnt3a⁺ CSC-like cells and restoration of TNFα⁺CD8⁺ TRMs. Finally, transcriptomic analysis of publicly available melanoma cohorts showed that enrichment of the Wnt pathway correlates with poor prognosis and ICB resistance, highlighting this pathway as a potential druggable negative regulator of ICB efficacy in melanoma.

Colorectal cancer (CRC) remains a formidable clinical challenge, many patients exhibit limited responses to conventional chemotherapy and targeted therapies. Although immunotherapy has demonstrated potential, its efficacy is largely restricted to a subset of patients with high microsatellite instability (MSI-H), highlighting the critical need to identify key molecular drivers of immune evasion in CRC. Through comprehensive bioinformatic analysis, we identified the deubiquitinating enzyme JOSD2 as a key player in CRC progression, with elevated expression correlating with poor prognosis in MSI-H patients (HR = 4.79, 95% CI: 3.6-7.96) and dysregulation of multiple immune-related pathways. Mechanistically, we discovered that JOSD2 suppresses cGAS enzymatic activity by removing K27-linked ubiquitination, thereby promoting M2 polarization of macrophages, a process critical for immunosuppression in the tumor microenvironment. Furthermore, using the JOSD2 catalytic inhibitor HY041004, we demonstrated both in vitro and in vivo that the inhibition of JOSD2 activated the cGAS-STING signaling pathway, leading to robust anti-tumor effects in CRC. These findings not only uncover a novel immunomodulatory mechanism in colorectal cancer but also provide a therapeutic rationale for the development of JOSD2-targeted anticancer strategies.

Gastroesophageal junction (GEJ) adenocarcinoma is an increasingly common cancer with complex biology and poor prognosis. The treatment strategy for locally advanced tumors involves multimodal treatment with perioperative chemotherapy. However, survival rates remain low, especially for advanced disease. Here, formalin-fixed paraffin-embedded tumor sections from 72 patients with GEJ I and II adenocarcinoma who underwent primary resection or perioperative standard-of-care FLOT treatment were analyzed for their intratumoral T cell composition using multiplex immunohistochemistry. The proportions of T cells and their influence on survival were evaluated using Mann-Whitney U and log rank analyses. A comparison of short- and long-term survivors revealed significant differences in the infiltration of regulatory T cells (Tregs). Tumors after neoadjuvant FLOT treatment presented increased proportions of CD8⁺ T cells with reduced Granzyme B expression, indicating an altered immune response. Overall survival analysis revealed that high infiltration of Tregs was associated with poor survival. Notably, responders to FLOT therapy had a greater T cell frequency and improved survival, whereas nonresponders presented higher levels of Tregs and CD8⁺ T cells expressing TIM-3. Overall, GEJ cancer patients had increased CD8⁺ T cells after neoadjuvant chemotherapy with FLOT, and Tregs were associated with treatment response and reduced survival.

SLAMF8 is predominantly expressed in macrophages and plays an important role in autoimmune diseases and inflammation. Our previous studies have focused on SLAMF8, however, the potential of SLAMF8 as an immunotherapeutic target and its role in regulating the tumor immune microenvironment remain to be elucidated. This study demonstrated that macrophage-specific SLAMF8 is significantly associated with a poor prognosis for colorectal cancer (CRC). Additionally, M2 macrophage and tumor-associated macrophages (TAMs) models were used to verify that SLAMF8 induces an immunosuppressive phenotype in macrophages and regulates antitumor immunity by inhibiting the activation and function of CD8+ T cells. In vivo, we confirmed that SLAMF8 inhibition promoted remodeling of the immunosuppressive microenvironment and augmented immunotherapy sensitivity in CRC. Mechanistically, we demonstrated that SLAMF8 promotes the polarization of macrophages toward the M2 phenotype via the PI3K/AKT and JAK/STAT3 signaling pathways. In summary, this study confirmed that inhibiting SLAMF8 exerts an antitumor effect by reversing the immunosuppressive tumor microenvironment in CRC, providing new therapeutic targets and strategies for combined immunotherapy.

The fibroblast activation protein alpha (FAPα) is overexpressed in the tumor microenvironment of most solid cancers and, in some cases, in cancer cells, making it an interesting target for theranostic applications. T-cells modified to express a chimeric antigen receptor (CAR) against FAP have recently been described. We previously established the UniCAR system, in which UniCAR T-cells can be repeatedly switched on and off via dosing with a bifunctional adaptor molecule, known as target module (TM). Here, we describe the first FAPI-based immunotheranostic UniCAR TMs (FAPI TMs), enabling both non-invasive molecular imaging and UniCAR T-cell immunotherapy. The FAPI TMs consist of the UAMC-1110 FAPI moiety, the NODA-GA chelator for copper-64 labeling, and the UniCAR epitope (E5B9). Following computational analyses, three FAPI TMs with polyethylene glycol (PEG) spacers of either four, twelve, or 24 units were synthesized. Although the three novel TMs specifically accumulate in FAP-positive tumors in xenograft mice, only the FAPI TMs with an extended spacer (PEG₁₂ and PEG₂₄) redirect UniCAR T-cells to FAP-positive target cells both in vitro and in an immunodeficient mouse model. In line with the computational studies, the E5B9 epitope is not accessible for binding when the PEG₄-based FAPI TM is bound to FAP. Our work demonstrates that the length of the spacer in FAPI TMs is critical for the effective redirection of UniCAR T-cells to FAP-positive cells. Overall, our novel FAPI TMs may represent highly promising immunotheranostic tools for personalized non-invasive diagnostic imaging and immunotherapy of cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune checkpoint inhibitors (ICIs), representingindicating an unmet clinical need. Hyperthermia therapy, an approved anti-cancer approach with limited adverse effects, has been suggested to be capable of modulating the tumor microenvironment (TiME). This study examined the potential of microwave hyperthermia (Ht) to restructure the TiME of Pan02 PDAC model and restore Pan02 tumor's sensitivity to ICIs, followed by mechanistic investigation. In vitro experiments were performed using a 41 °C water bath, and in vivo studies established the Pan02 murine model treated with 41 °C microwave hyperthermia + /- αPD-L1 therapy. In Ht-treated cells, increased percentages of nucleus envelope blebbing, micronucleation, and multi-/macro-nucleation were observed, and live imaging studies suggested mitotic catastrophe. Ht induced cGAS-STING activation, γH2AX formation, dsDNA release, and genomic damage (comet assay) in a time-delayed fashion 24-48 h after Ht. In the Pan02 model, the Ht and αPD-L1 combination significantly repressed the growth of Ht-treated and abscopal tumors and prolonged mouse survival. The TiME was significantly altered after Ht, featuring upregulated infiltration and maturation of DCs, CD8 + T cells, M1 macrophages, and activated cGAS-STING-IFN signaling. The addition of a STING antagonist abolished this tumor-suppressive effect. SUMO1 expression was significantly repressed after Ht, whereas SUMO1 overexpression attenuated Ht-induced cGAS-STING activation. The effect of Ht has also been validated in certain human PDAC cell lines. Taken together, our study suggests that microwave hyperthermia could be an excellent therapeutic companion of ICIs for PDAC management, associated with a novel mechanism of Ht-induced time-delayed DNA damage and STING activation.

The recent FDA approval of lurbinectedin plus atezolizumab for advanced small cell lung cancer underscores the promise of combining immunogenic cell death (ICD) inducers with PD-1/PD-L1 blockade. This synergistic strategy induces durable responses in refractory tumors and may extend immunotherapy benefits across diverse malignancies through rational ICD-checkpoint inhibitor combinations.