Oncoimmunology最新文献

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.

CD91 serves as a receptor that causes the activation of antigen-presenting cells in response to cancer cells by binding HSPs. In this context, the HSP-CD91 axis is responsible for the rejection of emerging and nascent cancers. The role of CD91 in the cross-presentation of HSP-chaperoned peptides is well established, but its contribution to cell signaling and costimulation is less clear. We investigated CD91-mediated signaling with respect to cancer immunosurveillance by examining two key adaptor proteins, Fgr and AXL. To investigate the interactions between the β chain of CD91 and Fgr and AXL, AlphaFold was used to predict protein‒protein binding areas. Signaling was further investigated by examining NF-κB phosphorylation and cytokine production in iBMDMs with CRISPR-induced tyrosine mutations. Mice conditionally lacking Fgr and AXL in dendritic cells were assessed for their ability to control tumors in inducible and transplantable models of cancer. In silico or CRISPR-mediated disruption of key tyrosines within CD91 abrogates Fgr binding, NF-κB activation, and cytokine release. Using a DC-specific Fgr knockout mouse model, we revealed that loss of Fgr severely impaired tumor immunosurveillance, whereas AXL knockout resulted in a milder phenotype, suggesting a greater downstream role. Loss of Fgr also prevents the development of adaptive immunity to tumors following HSP immunization, but it has no impact on transplantable tumor growth. These findings elucidate key components of the CD91 signaling mechanism, advancing our understanding of how dying tumor cells initiate adaptive immune responses and providing a therapeutic target to enhance this pathway.

While recent advances in immuno-oncology have revolutionized cancer therapy, only a subset patients benefit from these treatments and achieve durable clinical responses. Biomarker-guided identification of patients likely to respond to immunotherapy could enable more effective management of various malignancies. To explore this, we took advantage of a Phase I trial evaluating the efficacy of antigen-engineered dendritic cell (DC) vaccine, administered either as monotherapy or in combination with high-dose interferon-α2b, in promoting anti-tumor immunity in melanoma patients. Liquid biopsies, including serum and peripheral blood mononuclear cells, and tumor biopsies were previously analyzed for predictive markers using Luminex, NanoString gene expression profiling and flow cytometry. Here, in vitro stimulation assays were conducted to assess arginase-1 production by circulating myeloid subsets. Of 73 serum analytes, serum arginase-1 (sArg1) most effectively distinguished melanoma patients with measurable disease from healthy donors. Elevated sArg1 levels in patients with active disease correlated with favorable responses to the vaccine and were associated with longer overall and progression-free survival. Integrated phenotypic, functional and metabolic analyses identified circulating CD14^-CD11c⁺ DC3 as the likely source of sArg1. These findings support the hypothesis that sArg1 may serve as a biomarker for responsiveness to cancer vaccine immunotherapy and reflect systemic myeloid cell fitness associated with enhanced anti-tumor immunity. Given the stability and accessibility of serum compared to cells or tissues, this assay could offer a method for assessing patient status, potentially improving stratification and clinical decision-making.

Immunotherapy with immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) patients only achieves response rates of 25%-30%, indicating the necessity of new therapies for non-responder patients. Since myeloid-related suppressive factors are associated with poor responses to ICI in a subgroup of HCC patients, modulation of these targets may improve response rates. Our aim was to characterize the expression of the efferocytosis receptor MERTK in HCC and to analyze its potential as a new therapeutic target. In HCC patients, MERTK was expressed by myeloid cells and was associated with poorer survival. In a murine HCC model with progressive myeloid cell infiltration, MERTK was detected in dendritic cells and macrophages with an activated phenotype, which overexpressed the checkpoint ligand PD-L1. Concomitant expression of PD-1 in tumor T-cells suggested the pertinence of combined PD-1/PD-L1 and MERTK blockade. In vivo experiments in mice showed that inhibition of MERTK improved the therapeutic effect promoted by anti-PD-1 or by ICI combinations currently approved for HCC. This effect was associated with enhanced tumor infiltration and superior activity of antigen presenting cells and effector lymphocytes. Our results indicate that MERTK may behave as a relevant target for immunotherapeutic combinations in those HCC patients with tumors enriched in a myeloid component.

We conducted a phase Ib/II clinical trial to evaluate the safety, feasibility, and clinical activity of combining pembrolizumab (anti-PD-1) with XL888 (Hsp90 inhibitor) in patients with advanced colorectal cancer (CRC). We hypothesized that this regimen would modulate soluble and cellular immune mediators and enhance clinical outcomes. The trial employed a 3 + 3 open-label design, with an expansion cohort at the recommended phase II dose (RP2D) in treatment-refractory, mismatch repair-proficient CRC patients. Comprehensive analyses of plasma cytokines, peripheral blood mononuclear cells (PBMCs), and spatial immune cell patterns in liver biopsies were performed to identify unique immune signatures resulting from the combined therapy. The combination of pembrolizumab and XL888 proved to be safe and feasible, with a subset of patients achieving stable disease, although no objective responses were observed in this heavily pre-treated population. Correlative studies revealed immunomodulatory effects in tumors and circulation, including a reduction in IL6⁺ cells and macrophages (CD68⁺) within metastatic liver tissue, alterations in blood CD3⁺ cells, and upregulation of numerous inflammatory plasma cytokines. These findings suggest local and systemic immune activation by the combination of pembrolizumab and XL888. While clinical activity was modest in treatment-refractory CRC patients, there were notable effects on the tumor immune environment and systemic immune modulation.

Regulatory T cells (Tregs) contribute significantly to the immunosuppressive nature of the tumor microenvironment which is a main barrier for immunotherapies of solid cancers. Reducing Treg numbers enhances anti-tumor immune responses but current depletion strategies also impair effector T cells (Teffs), potentially leading to reduced anti-tumor immunity and/or autoimmune diseases. CD137 has been identified as the most differentially expressed gene between peripheral Tregs and intratumoral Tregs in virtually all solid cancers. Further, CD137 is expressed by malignant cells of certain cancers, making it a potential target for tumor immunotherapy. Here, we report the development of a fully human anti-human CD137 antibody of the IgG1 isotype, clone P1A1, that induces antibody-dependent cell-mediated cytotoxicity (ADCC) in CD137⁺ Tregs and cancer cells. P1A1 cross-reacts with murine CD137 which allowed testing murine chimeric P1A1 in syngeneic murine tumor models where P1A1 significantly reduced the number of CD137⁺ Tregs and inhibited tumor growth in a murine hepatocellular carcinoma (HCC) and a melanoma lung metastasis model. P1A1 can also be internalized thus enabling it as a carrier for drugs to target CD137⁺ Tregs and cancer cells. These anti-cancer properties suggest a translation of P1A1 to human immunotherapy.