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Tumor-induced manipulations of myelomonocytic differentiation have been widely reported. Here, we describe the elicitation of a tumor-supportive cell type in a T lymphoma model in mice. We observed that the development of T lymphoma coincided with the appearance of a lymphoma-associated monocytic cell type (LAM) of host origin accompanied by a diminished dendritic cell (DC) population. RNA-sequencing and cytometric analyses revealed that LAMs shared markers with both DCs and with resident macrophages, most closely resembling monocyte-derived DCs (moDCs). The numbers of T lymphoma cells were negatively affected by reducing LAMs suggesting a helper function of LAMs for tumor growth. LAMs expressed Notch ligands, and treatments of lymphoma-carrying mice with Notch signaling-inhibitors LY3039478 and DAPT selectively decreased expansions of T lymphomas with or without Notch1 mutations, respectively. Mature LAMs did not proliferate in the periphery. Instead, their expansion resulted from altered myelomonocytic differentiation in the bone marrows of lymphoma-carrying mice with increases in common monocyte/DC precursors but with reduced granulocyte, monocyte and DC precursor populations. These data suggest that developing T lymphomas are capable of reprogramming monocyte/DC differentiation to increase the numbers of a tumor-promoting DC type, attract it to tumor locations and may engage in Notch ligand-dependent signaling to support lymphoma survival.
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Intradermal delivery of the Toll-like receptor (TLR)-9 agonist agatolimod/CPG7909, prior to sentinel lymph node (SLN) biopsy was previously shown to induce locoregional and systemic immunity, reduce tumor-involved SLN rates, and improve recurrence-free survival in patients with early-stage melanoma. Remarkably, men exhibited superior dendritic cell (DC) maturation. Here, we report on further sex-based differences in the immune response after intradermal administration of CPG7909, which included higher CD80/CD83 expression levels in conventional (c) DC subsets in men's as compared to women's SLN, as well as higher ex-vivo release levels of IL-1β, TNF, and IL-6 (all contributors to cDC activation) and Th1/Th2 cytokines. In an effort to identify a more effective DC-activating therapy for women, we compared the in-vitro effects of CPG7909 with those of the TLR7/8 agonist resiquimod/R848 on SLN single cells from female patients. R848 induced superior cDC subset activation and TNF, IL-6, IL-10, IL-12, IFNγ, and CXCL10 release. Correlation analyses suggested that IFNα, TNF, and IL-6 were key for CPG7909-induced LNR-cDC activation, whereas R848's effect appeared more cytokine-independent. We conclude that combining locally delivered CPG7909 and R848 in early-stage melanoma will ensure full-range DC subset activation and robust pro-inflammatory T-cell responses in melanoma SLN, independent of sex.
Aging impairs vaccine responses. Dai et al. reported that defective cDC2 migration in immunized old mice, diminishing humoral and cellular immunity. Oral yeast-derived nanoparticles restore DC migration and vaccine efficacy. These findings establish impaired DC migration as a key mechanism of age-related immune decline, introducing a noninvasive strategy to correct immunosenescence.
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Innate immunity constitutes the primary barrier against invading pathogens and plays a crucial role in coordinating the initiation and modulation of adaptive immune responses. Transglutaminase 2 (TG2), a ubiquitously expressed multifunctional enzyme, has recently been identified as a key regulator of innate immune signaling. Mounting evidence highlights TG2's involvement in modulating type I interferons and pro-inflammatory cytokines in response to microbial infections and cellular stress, serving as an critical element in diverse signaling pathways. TG2 engages in various immune-related processes, such as inflammation, phagocytosis, and host defense, by integrating into essential intracellular signaling cascades. In this review, we synthesize the current knowledge of TG2's roles in the innate immune system, emphasizing its interactions with TBK1 (TANK-binding kinase 1)-a central node in type I interferon signaling-and other innate immune mediators. We also examine the implications of TG2 dysregulation in immune-mediated diseases and evaluate its promise as a therapeutic target. Collectively, this review integrates recent progress and encourages further exploration of TG2's multifaceted contributions to innate immunity.
Glioblastoma remains one of the most lethal malignancies, characterized by rapid recurrence, profound intratumoral heterogeneity, and a highly immunosuppressive microenvironment. Among immunotherapeutic strategies, peptide-based vaccines have attracted attention for their safety, specificity, and capacity to elicit tumor-directed T cell responses. Over the past two decades, several platforms targeting tumor-associated or tumor-specific antigens, including EGFRvIII, WT1, and survivin, have advanced into clinical trials. While early-phase studies demonstrated immunogenicity and occasional survival benefits, phase III trials have largely failed to confirm durable efficacy, underscoring the challenges posed by the ongoing complexity of tumor evasion mechanisms among which down regulation of MHC (HLA) expression in tumor cells, lack or reduced tumor antigen expression and a suppressive tumor microenvironment certainly play a role. As far as tumor antigens, recent insights also question the centrality of neoantigens, highlighting instead the immunogenicity of shared tumor-associated antigens, which may provide a more reliable foundation for broadly applicable vaccines in GBM. A major barrier to efficacy remains impaired antigen presentation, particularly the downregulation of MHC-II pathways. In this context, strategies leveraging the transcriptional activator CIITA to restore MHC-II expression hold promise both for reprogramming GBM cells into effective antigen-presenting cells and for the isolation of new families of MHC class II-bound peptides relevant for the triggering of tumor-specific CD4+ T cells. This new approach could pave the way for next-generation peptide vaccines, particularly when integrated with combinatorial modalities such as checkpoint inhibitors, myeloid-targeted therapies, or oncolytic viruses.
Standard of care radiotherapy and chemotherapy have shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). Immunotherapy has emerged as a promising treatment but has been hindered by systemic toxicities. A shift from systemic to localized delivery has reduced adverse effects and improved response rates in various cancers. However, the impact of tumor-targeted therapies on distant tissues, such as the bone marrow, remains underexplored. In a murine model of PDAC, we treated tumors with targeted stereotactic body radiation therapy (SBRT) and intratumoral interleukin-12 mRNA (IL-12). We evaluated tumor, blood, and bone marrow cells for therapy-induced changes over a period of 13 d to 13 months. Our results showed that while SBRT/IL-12 locally eradicated primary tumors, it also induced significant effects in the bone marrow. Early effects included acute lymphopenia in the blood and an immunostimulatory response in the bone marrow, leading to increased hematopoiesis. Long-term effects involved a reduction in hematopoietic stem cells (HSCs) and a shift towards a myeloid lineage, suggesting potential premature aging of the HSC population. These findings highlight the profound impact of localized SBRT/IL-12 therapy on distal bone marrow, emphasizing the need for further investigation into the long-term immunological consequences of localized cancer treatments.
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BET inhibitors (BETi) have shown potential to augment tumor immunogenicity in melanoma. However, conflicting evidence exists regarding their precise mechanism of action, and their overall impact on melanoma immunogenicity and antitumoral T cell responses remains unclear. To address this, human melanoma cell lines treated with JQ1 and/or IFNγ were investigated for gene and protein expression changes in key pathways governing immunogenicity and cocultured with autologous tumor-infiltrating lymphocytes (TIL) with known antigen-specificity. JQ1-induced proteome-wide alterations were examined using mass spectrometry-based cellular thermal shift assay (MS-CETSA), which revealed that JQ1 broadly impacts melanoma immunogenicity by regulating IFN signaling, antigen processing and presentation, and innate immune signaling pathways. More specifically, JQ1 enhanced JAK1/STAT1 signaling and upregulated components of the HLA class I (HLA-I) antigen processing and presentation machinery (APM), increased MART-1 expression while concomitantly dampening tumoral expression of PD-L1, IDO1, and HLA class II (HLA-II). Functionally, JQ1 markedly improved tumor recognition by autologous MART-1- and neoantigen-specific CD8+ TIL, while dampening CD4+ TIL activation through the downregulation of Cathepsin S (CTSS). Preliminary results using JQ1-treated melanoma cells in a mixed lymphocyte-tumor cell culture (MLTC) markedly enhanced TIL proliferation and resulted in a T cell product enriched for CD8+ T cells. These findings reveal how the pleiotropic effects of BETi on melanoma cells broadly boost their immunogenicity towards CD8+ T cells and uncover novel pathways that might be therapeutically exploited to enhance CD8+ T cell-mediated anti-tumor immunity in ex vivo and in vivo approaches to cancer immunotherapy.
Diffuse large B-cell Lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin's lymphoma for which current therapeutic strategies remain insufficient, in part owing to heterogeneity in tumor biology and the immune microenvironment. The diffuse nature of DLBCL represents a challenge to elucidate how malignant and immune cells are spatially organized within the tumor microenvironment (TME), and how this organization impacts immune function and clinical outcome. Here, we performed a pilot spatial transcriptomics analysis of primary DLBCL tissue sections to resolve spatial gene expression patterns and cell-cell interactions, with key cellular features validated at the protein level. We identified six recurrent, spatially organized cellular ecosystems (Cell-Eco) defined by distinct immune compositions, transcriptional programs, and neighborhood architectures. Notably, ecosystems with similar immune cell abundance exhibited divergent functional states and opposite clinical associations, demonstrating that spatial context and local interactions, rather than cell-type frequency alone, shape immune function within the DLBCL TME. Building on these spatial ecosystems, we derived Cell-Eco gene signatures that generated prognostic scores and robustly stratified patient survival in large, independent DLBCL cohorts comprising more than 1000 cases. Across ecosystems, tumor-associated macrophages have emerged as the dominant spatial partners of malignant B cells, highlighting their central role in structuring the immune microenvironment. Together, these findings establish a spatially informed framework for DLBCL immune organization and demonstrate the prognostic relevance of tumor cellular architecture.
Cancers of distinct histological subtypes are traditionally thought to arise from different cells of origin. However, alternative models propose that multipotent epithelial progenitors or late-stage transdifferentiation events may give rise to diverse tumor lineages, leaving the pathogenesis of adenosquamous carcinomas unresolved. Given the universal involvement of high-risk human papillomavirus in cervical carcinogenesis, cervical adenosquamous carcinoma offers a unique model to investigate tumor lineage relationships within a shared etiologic context. Here, we integrated histopathological, virological, and genomic analyses of microdissected glandular and squamous components from mixed tumors. Strikingly, both malignant elements displayed identical virological features and shared somatic alterations. Following early lineage separation, the two distinct (pre)cancerous entities evolved independently, exhibiting no component-specific mutational signatures. Taken together, these findings demonstrate that glandular and squamous populations from adenosquamous carcinomas follow independent evolutionary trajectories from a single progenitor cell, providing robust validation in human cancers of the concept of early clonal divergence.
While existing cancer therapies manage to reduce tumor burden, they often fail to produce durable or curative outcomes. Alternatively, cell-based approaches - particularly dendritic cell (DC) vaccines conceal the potential to elicit robust tumor-specific T-cell responses, equipping patients with T-cells capable of eradicating tumor cells and preventing future relapses. To date, most DC vaccines have been generated with monocyte-derived DCs (moDCs), nowadays considered less potent at priming T-cells than blood-derived DC subsets, arguing for the usage of blood DCs for vaccine development. However, their scarcity in blood has hindered their clinical application, limiting their use in DC-based vaccination trials. To overcome this limitation, we developed a protocol to generate clinically relevant quantities of conventional DC type 1 (cDC1s) and DC2-like cells (cDC2s) from progenitor cells isolated from peripheral blood without the need for G-CSF mobilization, enabling their use for autologous vaccinations. The protocol is feeder layer free, yields clinically relevant amounts of cDC1s and cDC2s-like cells, and can be translated into a GMP-compliant setup. The ex vivo-generated DCs resemble their natural counterparts, acquire a robust pro-inflammatory phenotype (e.g., CD83, CCR7, and IL-12p70), and efficiently expand pro-inflammatory T-cells (e.g., IFN-γ). Notably, in an in vitro immunization model, these DCs primed naive T-cells for the expansion of tumor-antigen-specific CD8 T-cells exhibiting strong immune-stimulating features (e.g., IFN-γ, CD107a). In summary, this study demonstrates that blood progenitors differentiate into cDC1 and cDC2-like cells capable of eliciting potent antigen-specific T-cell subsets, offering a promising avenue for the development of more effective DC-based cancer therapies.
Natural killer (NK) cells are cytotoxic innate lymphoid cells which directly kill tumor cells, thus represent an attractive target for immunotherapy. However, NK cells face immunosuppression in the tumor microenvironment (TME), rendering them dysfunctional. While cancer-associated fibroblasts (CAFs) represent an abundant, heterogeneous component of pancreatic ductal adenocarcinoma (PDAC), their interplay with NK cells is largely understudied. Analyzing human samples and employing mouse models of PDAC and functional assays, we observed that intratumoral NK cells are immature, and TGF-β driven myofibroblastic (my)CAFs are strong NK suppressors, in contrast to inflammatory (i)CAF. Furthermore, myCAF-enriched tumor areas excluded NK cells, consistent with their reduced capacity to attract NK cells. Pancreatic CAFs in general reduced NK cell cytotoxicity by direct contact and via soluble factors, including prostaglandin E2 (PGE2). This work reveals distinct and overlapping roles of CAF subpopulations on NK cell functions, suggesting that overcoming CAF-imposed barriers to NK cytotoxicity and tumor infiltration is essential to unleash their anti-tumoral properties.
Antibody-drug conjugates (ADCs) combine the target specificity of monoclonal antibodies with the cytotoxic potency of small-molecule payloads. In recent years ADCs have emerged as a clinically validated component of modern precision oncology. To date, more than a dozen ADCs have received FDA approval for oncologic indications, with additional agents approved regionally and hundreds of ADC-based regimens in clinical development. Collectively, these therapies have demonstrated clinical benefit across hematologic malignancies and solid tumors, including significant overall survival improvements in advanced phase clinical trials. In this Trial Watch, we provide an overview on available ADCs from early preclinical development to current clinical applications. We also summarize design principles underpinning clinically successful ADCs, including epitope targeting, linker chemistry, payload toxicity and drug-to-antibody ratio, and discuss how these features can influence pharmacokinetics, intracellular trafficking, bystander effect and toxicity. Finally, we discuss results from advanced-stage clinical trials and approved agents to define future directions.
Tumor-infiltrating lymphocyte (TIL) therapy, which involves extracting, expanding, and reinfusing immune cells to target cancer cells, has shown promise in melanoma treatment, but requires optimization for broader efficacy. The success of TIL therapy depends on the recognition of tumor-associated antigens, but neoantigen-reactive T-cells are often rare and exhausted in less immunogenic malignancies. Isolating T cells enriched in neoantigen reactivity prior to in vitro expansion and reinfusion may improve the response rates. To this end, our proprietary Specific Neo-Antigen Peptides (SNAP™) technology platform improves the accuracy of neoantigen prediction and validation by combining advanced computational modelling and PepSeq, a high-throughput screen for the physical credentialing of putative neoantigens based on their affinity to bind patient-specific HLA class II proteins. This approach allows for the education and enrichment of TILs (SNAP-TILs) with personalized, predefined, highly immunogenic neoantigens prior to expansion. Using the SNAP platform, we consistently achieved, on average, a SNAP-TIL product comprising 96% CD3+ cells, with a mixture of 75% effector and 23% central memory cells. SNAP-TILs exhibited greater efficacy and selectivity in immune infiltration than TIL, which was expanded by the rapid expansion protocol alone using ex vivo models. SNAP-TIL was also reactive in highly and poorly immunogenic tumors, with 70% and 50% tumor growth inhibition in melanoma and pancreatic patient-derived xenograft models, respectively. This study demonstrates the novel benefit of our Personalized Neoantigen Pipeline approach, potentially providing a durable antitumor immune response for a larger proportion of cancer patients.
Triple-negative breast cancer (TNBC) remains one of the most lethal breast cancer subtypes, driven by early dissemination and resistance to therapy. Here, we reveal a macrophage-centered cytokine circuit that fuels TNBC metastasis and immune evasion. Tumor cells reprogram naïve macrophages into tumor-associated macrophages (TAMs) that secrete CCL3, CCL4, CXCL2, and IL-1β, collectively promoting epithelial-to-mesenchymal transition, migration, transendothelial invasion, and lung colonization. These TAMs, in turn, convert naïve CD4⁺ T cells into FOXP3⁺ Tregs, establishing a self-reinforcing immunosuppressive niche. Pharmacological inhibition of CCR5, CXCR2, and IL1R1 with maraviroc, navarixin, and anakinra, respectively, disrupted this cytokine axis, suppressing metastatic colonization in vivo. Our findings reveal that blocking cytokine receptor signaling disrupts the pro-metastatic crosstalk between macrophages and TNBC cells, offering a clinically actionable strategy to restrain metastasis and overcome therapy resistance in TNBC.
Mesothelin (MSLN) is a GPI-anchored cell surface glycoprotein that is overexpressed in various solid tumors, including mesothelioma, triple-negative breast cancer, colon, ovarian and pancreatic cancer, with restricted normal tissue expression. To explore the immunogenicity and immunotherapeutic potential of MSLN to T cells with native receptor specificity, 29 individuals of diverse HLA backgrounds were interrogated for T cell activity against MSLN. Twenty one (72%) subjects (21/29) mounted a specific T cell response when repetitively challenged with MSLN antigen. Reactive cells were Th1-polarized, polyfunctional, predominantly detected in the CD8+ T cell compartment and cytotoxic toward autologous and MSLN+/HLA-matched tumor cell lines in conventional 2D in vitro assays. Furthermore, these cells produced anti-tumor effects in a novel 3D tumor spheroid model system established to evaluate the potency of reactive cells against tumors including pancreatic, cervical, and colorectal cancer and mesothelioma. These preclinical findings lay the groundwork for further exploration of MSLN as a potential immunotherapeutic target for T cells via the native T cell receptor.
Accumulating evidence implicates the microbiome as an important determinant of clinical outcomes in cancer therapies; however, the role of the microbiome in oncolytic virus therapy remains largely unexplored. We investigated the gut microbiome of cancer patients following treatment with the oncolytic adenovirus igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2; TILT-123). Baseline fecal samples from phase I clinical trials (NCT04695327 and NCT05271318) were analyzed using shotgun metagenomic sequencing and compared to treatment outcomes. A higher relative abundance of Alistipes was observed in patients with treatment benefit, while elevated Eggerthella was observed with reduced benefit. These associations were validated in a preclinical mouse model where administration of Alistipes shahii improved the efficacy of adenovirus therapy. In addition, enrichment analysis in patient samples showed a positive correlation between higher relative abundance of Alistipes and elevated short-chain fatty acids in both feces and serum, which in turn revealed higher circulating neutrophil counts. Finally, in a case study, we observed that adenovirus treatment resulted in increased Alistipes relative abundance and reduced Eggerthella relative abundance, indicating that adenovirus therapy may beneficially modulate the microbiome. Overall, our findings reveal a novel association between Alistipes, Eggerthella, and the therapeutic response to oncolytic adenovirus therapy, highlighting their potential as biomarkers or targets for microbiome-based interventions such as pre-, pro-, or postbiotics.
Anti-GD2 monoclonal antibodies (aGD2 mAbs) are the standard immunotherapy for patients with high-risk neuroblastoma. This treatment has improved 5-year overall survival; however, long-term efficacy still requires improvement. The "don't eat me" signal CD47 is upregulated on neuroblastoma tumor cells and inhibits aGD2 mAb effector mechanisms. Although GD2 is restrictively expressed on neuroblastoma tumor cells, CD47 expression is ubiquitous, resulting in an antigen sink and on-target off-tumor-related cytotoxicities. Recently, we developed two aGD2-SIRPα fusion mAbs for the murine and human settings. In vitro, these aGD2-SIRPα fusion mAbs restrict CD47 blockade toward GD2+ neuroblastoma tumor cells. In this study, we explored the tumor-targeting ability of aGD2-SIRPα fusion mAbs in a syngeneic 9464D-Luc-GFP and SK-N-AS xenograft neuroblastoma tumor model. Conventional aCD47 and aSIRPα mAbs encountered a dominant antigen sink in the 9464D-Luc-GFP model. Surprisingly, although aGD2 mAbs preferentially targeted tumors, murine aGD2-mSIRPα fusion mAbs accumulated in similar organs as aCD47 mAbs. Binding analysis of murine aGD2-mSIRPα and human aGD2-hSIRPα fusion mAbs to red blood cells (RBC) revealed strong binding of murine aGD2-mSIRPα to RBCs, whereas their human counterparts showed negligible binding. These data indicate species-specific CD47-SIRPα binding patterns. Utilizing a SK-N-AS xenograft model, we show effective tumor targeting of the human aGD2-hSIRPα fusion mAbs with hSIRPα in a C-terminal configuration. These data provide the first proof of principle for neuroblastoma tumor-targeted blockade of CD47 by aGD2-hSIRPα fusion mAbs in vivo and support the further development of aGD2-hSIRPα mAbs as attractive therapeutics to improve aGD2-based neuroblastoma immunotherapy.