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Sökning: WFRF:(Melssen Marit)

  • Resultat 1-7 av 7
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1.
  • He, Fei, et al. (författare)
  • FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-cell Exhaustion in a Sex-Dependent Manner
  • 2023
  • Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:10, s. 1628-1645
  • Tidskriftsartikel (refereegranskat)abstract
    • Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy.
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2.
  • Ingelshed, Katrine, et al. (författare)
  • MDM2/MDMX inhibition by Sulanemadlin synergizes with anti-Programmed Death 1 immunotherapy in wild-type p53 tumors
  • 2024
  • Ingår i: iScience. - : Elsevier. - 2589-0042. ; 27:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Immunotherapy has revolutionized cancer treatment but its efficacy depends on a robust immune response in the tumor. Silencing of the tumor suppressor p53 is common in tumors and can affect the recruitment and activation of different immune cells, leading to immune evasion and poor therapy response. We found that the p53 activating stapled peptide MDM2/MDMX inhibitor Sulanemadlin (ALRN-6924) inhibited p53 wild-type cancer cell growth in vitro and in vivo. In mice carrying p53 wild-type CT26.WT tumors, monotherapy with the PD-1 inhibitor DX400 or Sulanemadlin delayed tumor doubling time by 50% and 37%, respectively, while combination therapy decreased tumor doubling time by 93% leading to an increased median survival time. Sulanemadlin treatment led to increased immunogenicity and combination treatment with PD-1 inhibition resulted in an increased tumor infiltration of lymphocytes. This combination treatment strategy could potentially turn partial responders into responders of immunotherapy, expanding the patient target group for PD-1-targeting immunotherapy.
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3.
  • Melssen, Marit M., et al. (författare)
  • Barriers to immune cell infiltration in tumors
  • 2023
  • Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ Publishing Group Ltd. - 2051-1426. ; 11:4
  • Forskningsöversikt (refereegranskat)abstract
    • Increased immune cell infiltration into tumors is associated with improved patient survival and predicts response to immune therapies. Thus, identification of factors that determine the extent of immune infiltration is crucial, so that methods to intervene on these targets can be developed. T cells enter tumor tissues through the vasculature, and under control of interactions between homing receptors on the T cells and homing receptor ligands (HRLs) expressed by tumor vascular endothelium and tumor cell nests. HRLs are often deficient in tumors, and there also may be active barriers to infiltration. These remain understudied but may be crucial for enhancing immune-mediated cancer control. Multiple intratumoral and systemic therapeutic approaches show promise to enhance T cell infiltration, including both approved therapies and experimental therapies. This review highlights the intracellular and extracellular determinants of immune cell infiltration into tumors, barriers to infiltration, and approaches for intervention to enhance infiltration and response to immune therapies.
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4.
  • Melssen, Marit M., et al. (författare)
  • Peptide emulsions in incomplete Freund's adjuvant create effective nurseries promoting egress of systemic CD4(+) and CD8(+) T cells for immunotherapy of cancer
  • 2022
  • Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ Publishing Group Ltd. - 2051-1426. ; 10:9
  • Forskningsöversikt (refereegranskat)abstract
    • Water-in-oil emulsion incomplete Freund's adjuvant (IFA) has been used as an adjuvant in preventive and therapeutic vaccines since its development. New generation, highly purified modulations of the adjuvant, Montanide incomplete seppic adjuvant (ISA)-51 and Montanide ISA-720, were developed to reduce toxicity. Montanide adjuvants are generally considered to be safe, with adverse events largely consisting of antigen and adjuvant dose-dependent injection site reactions (ISRs). Peptide vaccines in Montanide ISA-51 or ISA-720 are capable of inducing both high antibody titers and durable effector T cell responses. However, an efficient T cell response depends on the affinity of the peptide to the presenting major histocompatibility complex class I molecule, CD4(+) T cell help and/or the level of co-stimulation. In fact, in the therapeutic cancer vaccine setting, presence of a CD4(+) T cell epitope seems crucial to elicit a robust and durable systemic T cell response. Additional inclusion of a Toll-like receptor ligand can further increase the magnitude and durability of the response. Use of extended peptides that need a processing step only accomplished effectively by dendritic cells (DCs) can help to avoid antigen presentation by nucleated cells other than DC. Based on recent clinical trial results, therapeutic peptide-based cancer vaccines using emulsions in adjuvant Montanide ISA-51 can elicit robust antitumor immune responses, provided that sufficient tumor-specific CD4(+) T cell help is given in addition to CD8(+) T cell epitopes. Co-treatment with PD-1 T cell checkpoint inhibitor, chemotherapy or other immunomodulatory drugs may address local and systemic immunosuppressive mechanisms, and further enhance efficacy of therapeutic cancer peptide vaccines in IFA and its modern variants. Blinded randomized placebo-controlled trials are critical to definitively prove clinical efficacy. Mineral oil-based adjuvants for preventive vaccines, to tackle spread and severity of infectious disease, induce immune responses, but require more studies to reduce toxicity.
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5.
  • Mohajershojai, Tabassom, et al. (författare)
  • PD-1 blockade enhances therapeutic effects of 177Lu-DOTA-M5A in colorectal cancer CEA-transgenic mice
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Radioimmunotherapy (RIT) is emerging as an effective treatment for metastatic solid tumors by coupling radionuclides with tumor-targeting molecules, precisely directing radiation to cancer cells while sparing healthy tissue. Carcinoembryonic antigen (CEA) is a promising target for RIT in CEA-expressing cancers, including colorectal cancers (CRCs). Recent studies highlight radiotherapy's role in enhancing the immune response against cancer. Combining RIT with immune checkpoint inhibitors, such as anti-PD-1 antibodies, may further enhance anti-tumor immunity and improve outcomes. This study aimed to investigate, for the first time, the in vivo effects of CEA-targeted RIT using the novel humanized anti-CEA antibody hT84.66-M5A labeled with 177Lu (177Lu-DOTA-M5A), combined with PD-1 blockade. Radioconjugate uptake and therapeutic effects were first assessed in vitro using the CRC spheroid model MC38-CEA1. The therapeutic effects of 177Lu-DOTA-M5A and PD-1 blockade were then evaluated alone or in combination in CEA-transgenic mice bearing CEA-transduced CRC xenografts, with radioconjugate uptake validated in biodistribution studies and visualized via SPECT/CT imaging. Dose-dependent therapeutic effects of 177Lu-DOTA-M5A were demonstrated in the 3D spheroid model. In vivo studies showed that both 177Lu-DOTA-M5A and PD-1 antibody monotherapies effectively reduced tumor growth rates compared to the control group, but the combination therapy had the most significant impact. Combination therapy resulted in a dramatic tumor growth inhibition rate of -6% average daily, compared to +7%, +7.9%, and +13.5% in the PD-1 blockade, 177Lu-DOTA-M5A (2.5 MBq), and control groups, respectively. Median survival increased by 31% in the PD-1 blockade group and by 52% in the 177Lu-DOTA-M5A (2.5 MBq) group compared to the control group, while median survival was not reached in the corresponding combination group. Radioconjugate monotherapies and combination therapies did not introduce any bone marrow toxicity. 177Lu-DOTA-M5A slightly altered the immune cell profile in the tumor microenvironment, increasing cytotoxic and helper T cells. Notably, pro-inflammatory macrophages became dominant over tumor-promoting ones in the tumor microenvironment of combination-treated mice. These findings highlight the promise of 177Lu-DOTA-M5A as a CRC therapeutic agent and its enhanced efficacy when combined with an immune checkpoint inhibitor. Further in vivo studies are needed to fully validate these findings and explore the treatment’s potential for clinical use.
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6.
  • Sarhan, Dhifaf, et al. (författare)
  • 885 Targeting FPR2 as a novel approach for immunotherapy in pancreatic cancer female patients : studies of sexual immune dimorphism in the tumor microenvironment
  • 2021
  • Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 9:Suppl 2, s. A927-A927
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundImmunotherapy for pancreatic cancer (PC) is inefficient due to a highly immune-suppressive tumor microenvironment (TME) orchestrated by myeloid suppressor cells, which limit the infiltration and function of cytotoxic immune cells. We have evidence that accumulation of a subpopulation of myeloid cells in human pancreatic lesions is associated with immune-exclusive tumor phenotype and effector T cell exhaustion by mechanisms involving the G-coupled protein receptor formyl peptide receptor 2 (FPR2), exclusively in women. We hypothesize that female FPR2+ myeloid cells in tumors induce immune exhaustion and contribute to immune-cold tumor phenotype.MethodsTo test our hypothesis, we first investigated the FPR2 RNA and protein expression in PC transcriptomic data and in murine and human PC tissues. Further, in vitro cytokine differentiated, alternatively tumor conditioned myeloid cells (TCM) were co-cultured with T cells to mimic their interaction in the TME. In vivo, PC cells were injected subcutaneously in FPR2 WT and KO mice to study tumor progression and the immune landscape in male vs. female mice. Later, human myeloid cells were treated with FPR2 agonists and antagonists to study the interaction mechanisms in detail.ResultsWe found high FPR2 expression in tumor compared to healthy tissues and higher in women compared to men. In mice and human, FPR2+ myeloid cells were associated with immune cold-exclusive and cold-ignored tumor phenotype in women and men, respectively. Notably, analysis in PC and other gastrointestinal (GI)-tract cancers revealed a significant association of FPR2 expression and poor survival only in women, emerging the potential impact of sex factors in the TME. Such sexual dimorphism in the TME was associated with T cell exhaustion apparent by high expression of TIM3 and PD1. In vitro, FPR2-agonist treated myeloid-suppressive cells induced TIM3 and PD1 expression in T cells specifically in female T cells. However, a significant repression of TIM3 and a trend of PD1 expression was observed in T cells when interacting with FPR2-inhibited or -deficient myeloid cells. Finally, tumor progression was significantly slower in FPR2 KO female mice compared to WT and male FPR2 WT and KO mice.ConclusionsIn this study, we have shown that sex differences are involved in shaping the TME in PC, where sexual dimorphism is still a largely unknown area allowing novel personalized/sex-specific immunotherapies. We found that FPR2 is highly involved in T cell exhaustion and can potentially be a therapeutic target for immunotherapy in women developing PC and other GI-tract cancers.
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7.
  • Sjöberg, Elin, et al. (författare)
  • Endothelial VEGFR2-PLCγ signaling regulates vascular permeability and antitumor immunity through eNOS/Src
  • 2023
  • Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 133:20
  • Tidskriftsartikel (refereegranskat)abstract
    • Endothelial phospholipase C gamma (PLC gamma) is essential for vascular development; however, its role in healthy, mature, or pathological vessels is unexplored. Here, we show that PLC gamma was prominently expressed in vessels of several human cancer forms, notably in renal cell carcinoma (RCC). High PLC gamma expression in clear cell RCC correlated with angiogenic activity and poor prognosis, while low expression correlated with immune cell activation. PLC gamma was induced downstream of vascular endothelial growth factor receptor 2 (VEGFR2) phosphosite Y1173 (pY1173). Heterozygous Vegfr2Y1173F/+ mice or mice lacking endothelial PLC gamma (Plcg1iECKO) exhibited a stabilized endothelial barrier and diminished vascular leakage. Barrier stabilization was accompanied by decreased expression of immunosuppressive cytokines, reduced infiltration of B cells, helper T cells and regulatory T cells, and improved response to chemo-and immunotherapy. Mechanistically, pY1173/PLC gamma signaling induced Ca2+/protein kinase C-dependent activation of endothelial nitric oxide synthase (eNOS), required for tyrosine nitration and activation of Src. Src-induced phosphorylation of VE-cadherin at Y685 was accompanied by disintegration of endothelial junctions. This pY1173/PLC gamma/eNOS/Src pathway was detected in both healthy and tumor vessels in Vegfr2Y1173F/+ mice, which displayed decreased activation of PLC gamma and eNOS and suppressed vascular leakage. Thus, we believe that we have identified a clinically relevant endothelial PLC gamma pathway downstream of VEGFR2 pY1173, which destabilizes the endothelial barrier and results in loss of antitumor immunity.
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