Inflammatory gene signature

P2/3, N=26, Not yet recruiting, Prof Curdin Conrad

Integrative predictors could include tumor mutational burden (TMB), inflammatory gene signature, phenotype of tumor-infiltrating lymphocytes, tumor microenvironment (TME), and immune checkpoint receptor expression on both immune and target cells. Additionally, the gut microbiota has recently been recognized as a systemic immunomodulatory factor and could further be used in the optimization of individualized immunovirotherapy algorithms.

Activation of this pathway is targetable using Ibrutinib and partially mitigated bortezomib resistance in an REIIBP xenograft model. Mechanistically, REIIBP upregulated TLR7 through eIF3E, and this relied on eIF3E RNA-binding function instead of its canonical protein synthesis activity, as demonstrated by direct binding to the 3'UTR of TLR7 mRNA. Altogether, we provided a rationale that coexistence of different NSD2 isoforms induced diversified oncogenic programs that should be considered in the strategies for t(4;14)-targeted therapy.

RAS mutations also decrease efficacy of the BCL2 inhibitor venetoclax now widely used in AML, suggesting an anti-apoptotic influence of MAPK signaling...Using GSEA we found that gilteritinib stimulated adaptive interferon/inflammatory gene signatures at 16h drug treatment, but this response was restrained by addition of SEL120...We speculate this latter effect may in part alter an AML cell's differentiation state to sensitize cells to apoptosis, though further study to explore this hypothesis is needed. Our in vitro and in vivo efficacy data further validated combined FLT3i/CDK8i as a promising investigational strategy to pre-empt or overcome MAPK-mediated FLT3 TKI resistance.

Our results suggest that the low-risk aAML patients were characterized by a more mature hematopoietic cell gene expression signature and cell surface markers as well as a pro-inflammatory state. Our study supports the possibility that pro-inflammatory cytokines and/or signaling could mediate AML cell survival in the low-risk aAML patient group. The high-risk aAML patients were characterized by a more primitive hematopoietic and leukemic stem cell gene expression signature.

This retrospective subgroup analysis of patients in the COMMANDS trial with the most frequent CHIP-related mutations (DNMT3A, TET2, ASXL1, and SF3B1) demonstrated novel effects of luspatercept in clonal hematopoiesis-related consequences including improvements in anemia, cytopenias, and reduced inflammation. Most importantly, NT-proBNP and elevated hepcidin levels were significantly downregulated in responders following luspatercept treatment. These results warrant evaluation of luspatercept in patients with high-risk CHIP mutations including clonal cytopenia of undetermined significance and patients with anemia of inflammation.

Additionally, ATX was significantly correlated with inflammatory gene signatures, including a CD8+ cytolytic score in multiple lung adenocarcinoma patient data sets, suggesting that an activated tumor-immune microenvironment upregulates ATX and thus provides an opportunity for cotargeting to prevent acquired resistance to anti-PD-1 treatment. These data reveal the ATX/LPA axis as an immunosuppressive pathway that diminishes the immune checkpoint blockade response in lung cancer.

We conclude that the dominant T-cell dysfunctional state in CLL is more fitting with senescence rather than exhaustion. These two T-cell states arise by distinct mechanisms and also require different means of reinvigoration in the context of immunotherapy. MAPK/p38 signaling is specifically activated in senescent cells, which could also be activated by DNA damage.

Conclusions AXA-042 demonstrates on-target biological activity in patient blood samples. Further biomarker analyses are ongoing and will be correlated with clinical activity in a larger number of patients.

Findings from this study will improve our understanding of how leukemic cells exploittheir TME to escape immune surveillance in the different patients and identify new vulnerabilities to be exploited for personalized therapeutic approaches. Acute myeloid leukemia, Relapse, OMICS, Allogeneic hematopoietic stem cell transplant

As this is likely triggered by leukemic cytokines, we found that leukemic serum dampens ex vivo NK cell degranulation capacity. Thus, we speculate that NK cells are sensitive to CML-associated cytokines and that inflammation represents an optimal target for NK-boosting immunotherapies.

Findings are under validation in a larger cohort, including early-stage NSCLC samples from Manchester’s early-detection screening studies and mapping of the immune contexture of PTI high versus low tumours is underway. 1: Ayers, M., et al., J Clin Invest., 2017 2: Danaher, P., et al., J Immunother Cancer., 2018 3: Banik, G., et al., Methods Enzymol., 2020

Bone marrow-derived macrophages (BMDMs) isolated from C57BL/6 mice were pre-treated with HDAC6 (NexturastatA) or HDAC11 (FT895) inhibitors prior to polarizing them to M1 and M2 phenotypes...Transcriptomics and single-cell secretome analyses of macrophages indicate that HDAC6 and HDAC11 affects macrophage function in diametrically opposite directions. Therefore, our study underscores the importance of class-selective inhibition of HDACs over pan-HDAC inhibitors and the potential use of selective HDAC inhibitors as a therapeutic option to control macrophage phenotype in cancer and other conditions.

The risk scores were significantly lower in patients who responded to immunotherapy (complete response/partial response - CR/PR) than in patients who did not respond to immunotherapy (stable disease/progressive disease - SD/PD). We developed and validated an inflammatory risk model, which served as an independent prognostic indicator and reflected immune response intensity in the BC microenvironment.

Human CML LT-HSC with low or absent c-Kit expression were markedly enriched after TKI treatment. We conclude that CML LT-HSC expressing low c-Kit levels are enriched for primitive, quiescent, drug-resistant leukemia initiating cells and represent a critical target for eliminating disease persistence.

This signature contained several members of the TNF superfamily, including those comprising the HLA Class III cluster (LTB, LST1, NCR3, LTA, and NFKBIL1). Our findings suggest that FBXW7β expression drives proinflammatory responses, which could contribute to normal B-cell development, leukemogenesis and responses to anti-cancer therapies.

Conclusions In CheckMate 592, high tTMB and bTMB were associated with better responses to 1L NIVO + IPI in pts with mNSCLC. Exploratory analyses suggest that tumor inflammation, measured by 4-gene inflammatory gene signature score, may increase with NIVO + IPI treatment.

Contradictory, low and high-dose TRT decreased CD4pos T helper 1 (Th1)-cells in addition to double negative T-cells. In conclusion, these data suggest that low and high-dose TRT induce distinct immunological changes, which might serve as an anchoring point for combination therapy.

The development of effective IDH1-targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our HLA-A2/HLA-DR1-syngeneic IDH1 glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.

Our novel 8-GRIP signature can accurately predict the prognosis of patients with CM and the efficacies of multiple anticancer therapies. These GRIPs might be potential prognostic biomarkers and therapeutic targets for CM.

Our data highlights new genomic signatures that indicate potential new, while also validating current targets for BRAFmut PTC: higher PD-L1 expression, immune infiltrate, and inflammatory gene signature. Clinical trials are needed to assess the best sequencing of therapies used in this group, particularly TKIs vs BRAF inhibitors and the role of immunotherapy.

 Our work represents the first scRNAseq and CITE-seq of cancer patient urine. Our study shows several immune cells shed in bladder cancer patient urine and suggests they look phenotypically similar to the TIME. This has implications for future clinical applications as urine can be sampled non-invasively in scenarios when tumor resection may not be feasible.

Understanding tissue-of-origins immune microenvironment has a potential contribution to early cancer detection. We anticipate this work provides evidence of how myeloid cell plasticity induces tumorigenesis and can shape different tumor microenvironments.

Tregs in CRC are associated with multiple pro-cancer pathways, but also with immune cell infiltration and immune response, as well as response to chemotherapy, particularly in metastatic tumors. Learning Objectives: Describe the role of regulatory T cells in moderating the host immune response to cancer cells. Understand the differences in gene expression between colorectal cancers which are infiltrated by a high versus low proportion of regulatory T cells.

Finally, we show that in highly purified human bone marrow samples from anaemic patients, imiquimod leads to an increase in erythroid output from myelo-erythroid progenitors and common myeloid progenitors. Our findings have both specific implications for the development of targeted therapeutics for del (5q) MDS and wider significance identifying a potential role for TLR7 ligation in modifying anaemia.

This study suggests a greater association of PD-L1 expression by CPS with NIVO{plus minus}IPI efficacy compared with %TC PD‑L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO{plus minus}IPI response, warranting further investigation.