P2, N=134, Active, not recruiting, Coherus Biosciences, Inc. | Recruiting --> Active, not recruiting

Our results suggest that loss of IL-27p28 suppresses colorectal tumorigenesis by augmenting CD8 T cell-mediated anti-tumor immunity. Targeting IL-27p28 could be developed as a novel strategy for the treatment of colorectal cancers.

P1, N=260, Recruiting, Coherus Biosciences, Inc. | Trial completion date: May 2024 --> Aug 2026 | Trial primary completion date: May 2024 --> Dec 2025

The sST2, cannot predict death in critically-ill patients as a single prognostic factor. However, the combination of at least two biomarkers: IL-33, sST2, IL-27, and galectin-3, gives very significant results in predicting the outcome in patients admitted to ICUs.

IL30 regulates the crosstalk between PC and EC and reshapes their transcriptional profiles, triggering angiogenic, immunoregulatory and oncogenic gene expression programs. These findings highlight the angiostatic and oncostatic efficacy of targeting IL30 to fight PC.

Clinical Trial Registration Number NCT05359861 Sponsored by Surface Oncology Background: Casdozo is the first in class and only clinical-stage IL-27 targeting antibody, which neutralizes IL-27 in the tumor microenvironment and stimulates antitumor response. Triplet blockade of the IL-27, VEGF, and PD-(L)1 pathways with casdozo/atezo/bev has an acceptable safety profile to date with promising antitumor activity in uHCC that warrants continued exploration. Toxicity was consistent with the known profiles of the agents, with no new safety signals identified. Biomarker analysis to evaluate immune response and associations of IL-27 pathway and clinical outcomes is ongoing.

IL-27 can induce the expression of miR-206 in MSCs, and miR-206 can be transported into FLS through MSC-EVs to promote FLS migration and MMP3 expression and aggravate articular cartilage damage. Patients with RA who have a high IL-27 expression may not be suitable to receive treatment with MSCs, and clinicians can use MSCs that knock down or delete IL-27R to treat RA patients who have a high IL-27 expression.

We discovered that T cells bearing scIL-27 sustained anti-tumor immunity and cytotoxicity yet manifested a profound reduction in pro-inflammatory cytokines granulocyte-macrophage colony-stimulating factor and tumor necrosis factor alpha. IL-27-expressing T cells therefore present a potential avenue to avert treatment-related toxicities commonly associated with engineered T-cell therapy due to the reduced pro-inflammatory cytokine profile.

Finally, we detected a decrease in IL-27 serum levels during CLL development in both pre-clinical and patient samples. Altogether, we demonstrated that IL-27 has a strong antitumorigenic role in CLL and postulate this cytokine as a promising treatment or adjuvant for this malignancy.

This model has a bias-corrected area under the receiver operating characteristic (ROC) curve (AUC) of 0.948, a sensitivity of 92.11%, a specificity of 93.33%, and an accuracy of 0.925. Our findings suggest that serum cytokines have the potential to be utilized in HCC screening to improve detection rates.

We further demonstrated that these NK cells killed PC3 cells in a partially TRAIL-dependent manner. This work provides mechanistic insight into how the cytotoxic function of NK cells can be improved to target cancer cells.

Through phenotyping these populations, I found IL-27 signaling induced Tfh-like PD-1+ICOS+ CD4 effector T cells and PD-1+ICOS+CD39+ exhausted-like CD8 T cells in the glands of recipient mice. Taken together, these data demonstrate a role for IL-27 in promoting pathogenic T cells in the immune dysregulation of Sjögren’s.

The acute bends at both signaling receptors in all complexes bring the membrane-proximal domains to a ~30 angstrom range but with distinct distances and orientations. We also reveal how CLCF1 engages its secretion chaperone cytokine receptor-like factor 1. Our data provide valuable insights for therapeutically targeting gp130-mediated signaling.

IL30 is a new CRC driver, since its inactivation, which disables oncogenic pathways and multiple autocrine loops, inhibits CR-CSC tumorigenicity and metastatic ability. The development of CRISPR/Cas9-mediated targeting of IL30 could improve the current therapeutic landscape of CRC.

In accordance, a subset of MM cell lines and primary MM cells cultured with IL-27 upregulated CD38 cell-surface expression, a finding with potential implications for enhancing the efficacy of CD38-directed monoclonal antibody (mAb) therapies by increasing CD38-expression on tumour cells. The elevated expression of IL-27Rα and JAM2 on MM cells compared to normal PCs may be exploited for the development of targeted therapeutic strategies that modulate the interaction of MM cells with the TME.

Moreover, miR193a-3p alters factors in MCF-7 secretome, which represses ERK1/2 and Akt phosphorylation, induces pro-apoptotic protein and apoptosis in LECs, and downregulates interferon-associated proteins known to promote cancer growth and metastasis. In conclusion, miR193a-3p can potentially modify the tumor microenvironment by altering pro-growth BC secretome and inhibiting LEC growth, and may represent a therapeutic molecule to target breast tumors/cancer.

Reverse MR analysis did not find the associations between genetic liability to prostate cancer and higher levels of IL-1ra (β, -0.005; 95% CI, -0.010, 0.001; P=0.111) and IL-6 (β, 0.002; 95% CI, -0.011, 0.014; P=0.755). This MR study suggests that long-term IL-6 may increase the risk of prostate cancer and IL-1ra may reduce it.

Furthermore, IL27 treatment improved breast cancer cell migration. The TIIS represents a promising prognostic tool for estimating OS in patients with breast cancer and is correlated with immune status.

The nomogram's 1-, 3-, and 5-year AUCs were .828, .783, and .751, respectively. Overall, our study developed an immune-related model and a nomogram that could reliably predict OS for breast cancer patients, and offered insights into tumor immune and pathological mechanisms.

Berberine appears to have a protective effect on disease development and alleviating disease status in EAE, which appears to be due to the cell expansion and function of Treg and Th2 cells in addition to berberine's anti-inflammatory properties.

These changes might be associated with the protective effect of Probio-M9 against mammary tumor growth. Thus, probiotic administration could harness host gut microbiome in anti-cancer responses.

A differential cytokine profile was found in serum and PF as IL-2, IL-8, IL-15, IL-27, IFN-γ, and GM-CSF were elevated specifically in PF. In conclusion, the differential immune profile and correlation of soluble parameters and NK cell receptors with chemo response score may add knowledge to understand anti-tumor immune response to develop effective treatment modality.

The mRNA expression was significantly decreased (P < 0.05), and the mRNA expression of IL-27 was significantly increased (P < 0.001), which did not affect the mRNA expression of lymphocyte proliferation and activation-related regulators. The tumor suppressor breast cancer 1 (BRCA1) and antimicrobial peptide CAMP were significantly increased, and decreased (P < 0.001), and the expression of pro-apoptotic factor Caspase9 showed a significant downward trend (P < 0.05).

At this timepoint, increases in levels of cytokines IFN-β, MCP-1 and IL-6 were observed following irradiation with 8 Gy in AB1 but not AE17, reflecting patterns in marker expression. Overall, this study establishes the dose- and time-dependent changes in immune marker expression of commonly studied mesothelioma cell lines following radiation and will inform future study into optimal dosing and scheduling of combined radiotherapy and immune checkpoint inhibition for mesothelioma.

In conclusion, HXZQ alleviated CAC in mice by modulating the intestinal microbiota and metabolism, activating Nrf2-mediated antioxidant response, and inhibiting NF-κB-mediated NLRP3 inflammasome activation against inflammation. The present data provide a reference for the use of HXZQ as a therapeutic or combination agent for clinical CAC treatment.

Membrane-anchored IL30 expressed by human PC cells shares a tumor progression programs with its murine homolog and, via juxtacrine signals, steers a complex network of PC driver and immunity genes promoting prostate oncogenesis. The efficacy of CRISPR/Cas9-mediated targeting of IL30 in curbing PC progression paves the way for its clinical use.

Moreover, the levels of IFN‑γ, TNF‑α, and IL‑17 displayed a noticeable reduction in the daphnetin treated group. Daphnetin appears to improve the disease by increasing the expression of anti‑inflammatory cytokines and transcription factors (IL‑4, IL‑10, IL‑33, GATA3, TGF‑β, FoxP3), and reducing the production of pro‑inflammatory cytokines and transcription factors (IFN‑γ, STAT4, T‑bet, IL‑17, STAT3, ROR‑γt, TNF‑α).

Future experiments will assess the functionality of CD39 + CD8 + T-cells using ex vivo cytotoxicity assays. Data generated in this study will provide novel information on the mechanism of CD39 induction and its effect on CD8 + T-cell function, which can be exploited to improve future cancer therapies.

Blocking IL-27 activity by SRF388, a first-in-class monoclonal antibody, enhances immune function and demonstrates monotherapy activity in patients with cancer ( NCT04374877 )...IL-27 + cells are found in close proximity to PD-L1 + cells in patient tumors, and IL-27 can regulate levels of PD-L1 expression in immune cells and tumor cell lines, suggesting cross-talk between these molecules to diminish immune activation within the tumor microenvironment. Combined blockade of IL-27 and PD-(L)1 to enhance antitumor immune responses is currently being evaluated in clinical trials.

The combined treatment enhanced NK-cell cytotoxicity against both PC3 and DU145 cells with concurrent enhanced STAT3 activation. 4-1BB antibody and IL-27 improved NKG2D agonist function in NK cells against prostate cancer cells.

Taken together, this cell line deals with two conflicting oncogenic drivers, namely, JAK2-STAT3 signaling and EBV infection, but is sensitive to switch after cytokine stimulation. Thus, AM-HLH represents a unique cell line model to study the pathogenic roles of STAT3 and EBV and their therapeutic implications in HL.

Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy.

Patients receiving both EGFR-TKIs and once-daily TRT were more likely to develop symptomatic RP than patients receiving concurrent chemoradiotherapy. The ilV30, tlV20, and comorbidity of COPD may predict the risk of symptomatic RP among NSCLC patients receiving EGFR-TKIs and conventionally fractionated TRT concurrently.

d-MAPPS in CXCL16-dependent manner promoted recruitment of antitumorigenic IFN-γ/IL-17-producing CD4+Th1/Th17 cells and in IL-27-dependent manner induced expansion of tumoricidal CD178+granzyme B-expressing CD8+CTLs and inhibited generation of tolerogenic DC, IL-10, and TGF-β-producing FoxP3-expressing T regulatory cells. In summing up, d-MAPPS, in CXL16- and IL-27-dependent manner, enhanced T cell-driven antitumor immune response and suppressed breast cancer growth in experimental mice.

Finally, we showed that RNA-seq-derived features are robust to the number of measured genes, showing potential for being derived from expression assays targeting a few hundred genes. Conclusion Our approach provides a high-level representation of the TME from commonly available data (RNA-seq and pathology slides), allowing us to obtain interpretable biomarkers covering different sets of mechanisms behind patient response to treatment.

Most importantly, intratumoral delivery of IL-12 and IL-27 mRNAs induced robust infiltration of immune effector cells, including IFN-γ and TNF-α producing NK and CD8 T cells into tumors. Thus, intratumoral administration of DAL-LNP loaded with IL-12 and IL-27 mRNA provides a new treatment strategy for cancer.

Intra-tumoral injection of Imiquimod, a TLR7/8 ligand, reduced the tumor burden; the anti-tumor effect was reversed upon IL-27 and IL-27R silencing by intra-tumorally administered, lentivirally expressed IL-27 and IL-27R shRNA. The reduced tumor growth was accompanied by significantly fewer Treg cells but increased IFN-γ and granzyme B expression by CD8 T cells. These data indicate the preventative role for TLR-induced IL-27 in aggressive and highly invasive melanoma.

Finally, in vitro killing assays showed an increased cytotoxicity of both human and murine T cells in the presence of IL-27, while serum protein quantification showed a decrease in the levels of IL-27 in both CLL patients (E) and sick mice (F) when compared to their healthy counterparts. Conclusion Overall, our results demonstrate the antitumor role of IL-27 in CLL development and progression by promoting T-cell-mediated anti-tumor immunity, as well as establish this cytokine as a potential immunotherapeutic agent in CLL.

SLC7A11 was negatively correlated with the expression of chemokines and chemokine receptors, such as CCL17, CCL19, CCL22, CCL23, CXCL14, CCR10, CX3CR1, and CXCR3, in COAD. SLC7A11 may play a role in induced ferroptosis and regulating tumor immunity, which can be considered as potential therapeutic targets in COAD.

We are using scRNA-seq methods to identify transcriptional changes in FLT3-ITD DCs that lead to the phenotypes we identified. Understanding how FLT3-ITD DCs contribute to AML immune suppression is critical to interpreting leukemia etiology and the development of targeted therapies such as immune checkpoint blockade or small molecule inhibitors.

To address this, we profiled 51 pre-treatment serum cytokines and chemokines to identify those that were differentially associated with response and survival in male vs. female relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with Axicabtagene ciloleucel. Male non-responders (stable/ progressive disease) had significantly higher baseline levels of IL-6, IL-8, IL-1RA, MIP-1α, GM-CSF and CRP compared to responders (complete/partial response)...Finally, baseline IL-8 and CRP were significantly correlated with baseline MTV and LDH levels in male but not female patients. Taken together, elevated baseline levels of IL-8, IL-6, CRP with high pretreatment tumor burden in male non-responder R/R LBCL patients point to an immunosuppressive tumor microenvironment that can potentially hinder anti-tumor activity prior to treatment and CAR T-cell expansion upon treatment in these patients, and result in poor outcomes.