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Abstract LB128: Timely resolution of TREM-1-mediated inflammation after chemotherapy improves complete response rate and survival in experimental pancreatic cancer

作者: Sigalov, Alexander B.

AbstractPancreatic ductal adenocarcinoma (PDAC), is the third leading cause of cancer-related death in the US. Despite recent advances, the 5-year survival rate for all stages combined is as low as 13%, necessitating the development of new approaches. Similar to other cancer treatments, current chemotherapy standard of care for PDAC represents a double-edged sword: it reduces tumor burden by killing cancer cells, however, the resulting dead tumor cells, or debris, induce inflammation that promotes tumor recurrence and metastasis. We hypothesized that blockade of triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation-amplifying receptor expressed on myeloid cells including tumor-associated macrophages (TAMs), can resolve chemotherapy-induced inflammation and improve response rate and survival. To address the problem of multiplicity and promiscuity of natural TREM-1 ligands and reduce the risk of drug failure in clinical efficacy testing, we developed a first-in-class TREM-1 inhibitory peptide sequence GF9 that employs a novel, ligand-independent mechanism of action. In this study, we used lipopeptide complexes (LPC) of a 31-mer peptide GA31 (GA31-LPC) to predominantly inhibit TREM-1 expressed on macrophages. GA31 is rationally designed to combine the TREM-1 inhibitory activity of a 9-mer peptide GF9 with the lipid-binding and macrophage-targeting capabilities of an oxidatively modified peptide PA22, a 22-amino acid amphipathic peptide that originates from human apolipoprotein A-I. Formulation of GA31 into LPC significantly extends its half-life and improves targeting. We found that the sub 120 nm-sized GA31-LPC formulation is stable, non-immunogenic, non-cytotoxic and well-tolerable, and effectively suppresses inflammation in vitro and in vivo. In xenograft mouse models of PDAC, TREM-1 blockade reduces plasma cytokines and TAM content and when started after standard chemotherapy, significantly improves complete response rate and survival. The magnitude of this effect depends on the chemotherapy agents used and their dosage. When started simultaneously with chemotherapy, TREM-1 blockade does not exhibit anti-tumor activity. In summary, this animal proof-of-concept study shows for the first time the critical importance of timing in the suppression of TREM-1-mediated inflammation in chemotherapy-treated cancers. This may have important clinical implications in the treatment of patients with not only PDAC, but also other inflammation-associated, hard-to-treat solid tumors. By supplementing current first-line cancer treatments (chemo- and immunotherapies, radiation and surgery), pharmacological interventions that timely resolve TREM-1-mediated inflammation may improve quality of life and extend survival of cancer patients.Citation Format:Alexander B. Sigalov. Timely resolution of TREM-1-mediated inflammation after chemotherapy improves complete response rate and survival in experimental pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB128.

2024-12-06·JCI Insight

Inhibiting triggering receptor expressed on myeloid cells 1 signaling to ameliorate skin fibrosis

Article

作者: Varga, John ; Yalavarthi, Bharath ; Silverman, Jenna N. ; Bajželj, Matija ; Shah, Kris A ; Silverman, Jenna N ; Sigalov, Alexander B ; Bale, Swarna ; Sigalov, Alexander B. ; Hasan, Syed A.M. ; Hasan, Syed Am ; Broderick, Katherine ; Hamill, Timothy ; Khanna, Dinesh ; Bhattacharyya, Swati ; Verma, Priyanka ; Shah, Kris A.

Systemic sclerosis (SSc) is characterized by immune system failure, vascular insult, autoimmunity, and tissue fibrosis. TGF-β is a crucial mediator of persistent myofibroblast activation and aberrant extracellular matrix production in SSc. The factors responsible for this are unknown. By amplifying pattern recognition receptor signaling, triggering receptor expressed on myeloid cells 1 (TREM-1) is implicated in multiple inflammatory conditions. In this study, we used potentially novel ligand-independent TREM-1 inhibitors in preclinical models of fibrosis and explanted SSc skin fibroblasts in order to investigate the pathogenic role of TREM-1 in SSc. Selective pharmacological TREM-1 blockade prevented and reversed skin fibrosis induced by bleomycin in mice and mitigated constitutive collagen synthesis and myofibroblast features in SSc fibroblasts in vitro. Our results implicate aberrantly activated TREM-1 signaling in SSc pathogenesis, identify a unique approach to TREM-1 blockade, and suggest a potential therapeutic benefit for TREM-1 inhibition.

2022-04-01·Biochimie3区 · 生物学

SARS-CoV-2 may affect the immune response via direct inhibition of T cell receptor: Mechanistic hypothesis and rationale

3区 · 生物学

Article

作者: Sigalov, Alexander B

During co-evolution with their hosts, many viruses have evolved a membrane fusion mechanism to facilitate host cell entry. Examples are human immunodeficiency virus type 1 (HIV-1) and severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2). These viruses can also infect immune cells (e.g., T cells), providing one of the possible mechanisms for the T cell lymphopenia observed in patients with these infections. Previously, we hypothesized and confirmed in vivo that like HIV-1, SARS-CoV-1 can use its fusion domain not only to enter the T cell but also to directly inhibit T cell receptor signaling. Here, based on the analysis of available structural and clinical data, we hypothesize that SARS-CoV-2 may use a similar "disarm the alarm" strategy to suppress immune responses. We also discuss the implications of this hypothesis for better understanding coronavirus disease 2019 (COVID-19) pathology, developing effective COVID-19 vaccines and improving clinical outcomes for COVID-19 patients.

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UHS-GBCA ( TREM1 )	-	临床前
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