A neutrophil response linked to tumor control in immunotherapy II
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE224400 | GEO | 2023/02/06
REPOSITORIES: GEO
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Project description:Neutrophils accumulate in solid tumors and their abundance correlates with poor prognosis. Neutrophils are not homogenous, however, and could play different roles in cancer therapy. Here, we investigated the role of neutrophils in immunotherapy leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sell-hi state, rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of antitumor immunity, including BATF3-dependent DCs, IL12 and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy.
2023-02-06 | GSE224399 | GEO
Project description:Neutrophils infiltrated in the tumor microenvironment (TME) are heterogeneous populations associated with the prognosis of cancer and cancer immunotherapy. However, the plasticity and function of heterogeneous neutrophils in the TME of non-small cell lung cancer (NSCLC) remain poorly understood. Here, we show that neutrophils produce high levels of IL-8 which induce the differentiation of CD74highSiglecFlow neutrophils and suppress the generation of CD74lowSiglecFhigh neutrophils in the TME of IL-8-humanized (IL8-hu) KrasLSL-G12DTp53fl/fl (KP) and EGFRT790M/Del-Exon19 (EGFRTD) NSCLC mouse models. The CD74highSiglecFlow neutrophils exhibit antigen cross-presentation activity to augment anti-tumor T cell responses. Consistently, deletion of CD74 in IL8-hu neutrophils attenuates the activation of T cells and exacerbates the progression of NSCLC, whereas treatment of a CD74 agonist promotes anti-tumor T cell activation and enhances the effects of anti-PD1 or Osimertinib therapy in the IL8-hu NSCLC mouse models. In addition, we have found that the CD74highCD63low neutrophils in the TME and peripheral blood of advanced NSCLC patients pheno-copy the CD74highSiglecFlow neutrophils in the TME of NSCLC mice and correlate well with the responsiveness to anti-PD-1 plus chemotherapies. Collectively, these data demonstrate an IL-8-CD74high neutrophil axis that promotes anti-tumor immunity in NSCLC.
2024-09-13 | GSE252460 | GEO
Project description:Neutrophils infiltrated in the tumor microenvironment (TME) are heterogeneous populations associated with the prognosis of cancer and cancer immunotherapy. However, the plasticity and function of heterogeneous neutrophils in the TME of non-small cell lung cancer (NSCLC) remain poorly understood. Here, we show that neutrophils produce high levels of IL-8 which induce the differentiation of CD74highSiglecFlow neutrophils and suppress the generation of CD74lowSiglecFhigh neutrophils in the TME of IL-8-humanized (IL8-hu) KrasLSL-G12DTp53fl/fl (KP) and EGFRT790M/Del-Exon19 (EGFRTD) NSCLC mouse models. The CD74highSiglecFlow neutrophils exhibit antigen cross-presentation activity to augment anti-tumor T cell responses. Consistently, deletion of CD74 in IL8-hu neutrophils attenuates the activation of T cells and exacerbates the progression of NSCLC, whereas treatment of a CD74 agonist promotes anti-tumor T cell activation and enhances the effects of anti-PD1 or Osimertinib therapy in the IL8-hu NSCLC mouse models. In addition, we have found that the CD74highCD63low neutrophils in the TME and peripheral blood of advanced NSCLC patients pheno-copy the CD74highSiglecFlow neutrophils in the TME of NSCLC mice and correlate well with the responsiveness to anti-PD-1 plus chemotherapies. Collectively, these data demonstrate an IL-8-CD74high neutrophil axis that promotes anti-tumor immunity in NSCLC.
2024-09-13 | GSE250409 | GEO
Project description:The characteristics of the tumor immunosuppressive microenvironment represent a major challenge limiting the efficacy of immunotherapy. Our previous results suggested that cryo-thermal therapy (CTT), a tumor ablation system developed in our laboratory, could promote macrophage M1-type polarization and full maturation of DCs to remodel the immunosuppressive environment. However, it is not clear which cells respond promptly to CTT. CTT can cause extensive cell death and the release of danger-associated molecular patterns (DAMPs) and antigens. Neutrophils are the first white blood cells recruited to sites of damage and acute inflammation. We therefore hypothesized that neutrophils were the initial cells to respond to CTT and were involved in the subsequent establishment of antitumor immunity. We found that CTT led to a rapid and strong proinflammatory neutrophil response, which was essential for the long-term survival of mice. In vivo neutrophil depletion and in vitro coculture experiments demonstrated that CTT-induced neutrophils promoted the differentiation of monocytes toward to mature antigen presenting cells and further upregulated the expression of IFN-γ and cytotoxic molecules in T and NK cells in a CD86-dependent manner. These results reveal the important role of neutrophil-monocyte interactions for the development of anti-tumor immunity and highlight that CTT could be used as an immunotherapy for targeting neutrophils and monocytes to enhance antitumor immunity.
2024-03-02 | GSE259010 | GEO
Project description:SARS-CoV-2 is a novel coronavirus that causes acute respiratory distress syndrome (ARDS), death and long-term sequelae. Innate immune cells are critical for host defense but are also the primary drivers of ARDS. The relationships between innate cellular responses in ARDS resulting from COVID-19 compared to other causes of ARDS, such as bacterial sepsis is unclear. Moreover, the beneficial effects of dexamethasone therapy during severe COVID-19 remain speculative, but understanding the mechanistic effects could improve evidence-based therapeutic interventions. To interrogate these relationships, we developed an scRNAseq atlas that is freely accessible (biernaskielab.ca/COVID_neutrophil). We discovered that compared to bacterial ARDS, COVID-19 was associated with distinct neutrophil polarization characterized by either interferon (IFN) or prostaglandin (PG) active states. Neutrophils from bacterial ARDS had higher expression of antibacterial molecules such as PLAC8 and CD83. Dexamethasone therapy in COVID patients rapidly altered the IFNactive state, downregulated interferon responsive genes, and activated IL1R2+ve neutrophils. Dexamethasone also induced the emergence of immature neutrophils expressing immunosuppressive molecules ARG1 and ANXA1, which were not present in healthy controls. Moreover, dexamethasone remodeled global cellular interactions by changing neutrophils from information receivers into information providers. Importantly, male patients had higher proportions of IFNactive neutrophils and a greater degree of steroid-induced immature neutrophil expansion. Indeed, the highest proportion of IFNactive neutrophils was associated with mortality. These results define neutrophil states unique to COVID-19 when contextualized to other life-threatening infections, thereby enhancing the relevance of our findings at the bedside. Furthermore, the molecular benefits of dexamethasone therapy are also defined. The identified molecular pathways can now be targeted to develop improved therapeutics.
2021-10-05 | PXD028429 | Pride
Project description:Neutrophils are essential cells of host innate immunity. Although the role of neutrophils in defense against bacterial and fungal infections is well characterized, there is relative paucity of information about their role against viral infections. Influenza A virus (IAV) infection can be associated with secondary bacterial co-infection, and it has long been posited that the ability of IAV to alter normal neutrophil function predisposes individuals to secondary bacterial infections. To better understand this phenomenon, we evaluated the interaction of pandemic or seasonal H1N1 IAV with human neutrophils isolated from healthy subjects. These viruses were ingested by human neutrophils and elicited changes in neutrophil gene expression that are consistent with an interferon-mediated immune response. Viability of neutrophils following co-culture with either pandemic and seasonal H1N1 IAV was similar for up to 18 h of culture. Notably, neutrophil exposure to seasonal IAV (but not pandemic IAV) primed these leukocytes for enhanced functions, including production of reactive oxygen species and bactericidal activity. Taken together, our results are at variance with the universal idea that IAV impairs neutrophil function directly to predispose individuals to secondary bacterial infections. Rather, we suggest some strains of IAV prime neutrophils for enhanced bacterial clearance.
2017-12-05 | GSE100865 | GEO
Project description:Immunotherapy is revolutionizing cancer treatment but can trigger toxicities that remain poorly understood. Here, by comprehensively analyzing mouse models following anti-CD40 therapy, we found an interdependent induction of the cytokines IFN-g and IL-12, which caused inflammatory pathology in various tumor-free tissues. In the liver, Kupffer cells mediated toxicity by sensing lymphocyte-derived IFN-g and producing IL-12, highlighting the vulnerability of tissue-resident macrophages to promote toxicity when reacting to proinflammatory cues. Conversely, dendritic cells drove tumor control but were dispensable for toxicity. We further show that liver macrophages, IL-12, and IFN-g were not toxic themselves, but prompted a neutrophil response that determined the severity of tissue damage. Similar inflammatory pathways characterized immunotherapy-related adverse events in cancer patients. These findings implicate resident macrophages and neutrophils as mediators and effectors of aberrant inflammation, and suggest distinct cellular mechanisms of toxicity and antitumor immunity.
2021-06-03 | GSE175737 | GEO
Project description:This ordinary differential equation model is the Panetta-Kirschner model of tumor-immune interactions is described in the publication:
Cappuccio A, Castiglione F, Piccoli B." Determination of the optimal therapeutic protocols in cancer immunotherapy." Math Biosci. 2007 Sep;209(1):1-13.
doi: 10.1016/j.mbs.2007.02.009.
Comment:
The model represented in Equations 1-3 is the Panetta-Kirschner model and was used to reproduce Fig. 1.
N.B.: Labelling of Fig. 1 graphs in manuscript mismatches with simulation results - CTL and tumor cell plots swapped.
Abstract:
Cancer immunotherapy aims at eliciting an immune system response against the tumor. However, it is often characterized by toxic side-effects. Limiting the tumor growth and, concurrently, avoiding the toxicity of a drug, is the problem of protocol design. We formulate this question as an optimization problem and derive an algorithm for its solution. Unlike the standard optimal control approach, the algorithm simulates impulse-like drug administrations. It relies on an exact computation of the gradient of the cost function with respect to any protocol by means of the variational equations, that can be solved in parallel with the system. In comparison with previous versions of this method [F. Castiglione, B. Piccoli, Optimal control in a model of dendritic cell transfection cancer immunotherapy, Bull. Math. Biol. 68 (2006) 255-274; B. Piccoli, F. Castiglione, Optimal vaccine scheduling in cancer immunotherapy, Physica A. 370 (2) (2007) 672-680], we optimize both the timing and the dosage of each administration and introduce a penalty term to avoid clustering of subsequent injections, a requirement consistent with the clinical practice. In addition, we implement the optimization scheme to simulate the case of multi-therapies. The procedure works for any ODE system describing the pharmacokinetics and pharmacodynamics of an arbitrary number of therapeutic agents. In this work, it was tested for a well known model of the tumor-immune system interaction [D. Kirschner, J.C. Panetta, Modeling immunotherapy of tumor-immune interaction, J. Math. Biol. 37 (1998) 235-252]. Exploring three immunotherapeutic scenarios (CTL therapy, IL-2 therapy and combined therapy), we display the stability and efficacy of the optimization method, obtaining protocols that are successful compromises between various clinical requirements.
2024-09-02 | BIOMD0000001036 | BioModels
Project description:Neutrophils are increasingly recognized as key players in the tumour immune response, and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Single-cell RNA sequencing (scRNAseq) of neutrophils from the bone marrow, spleen, and blood in addtion to the pancreatic tumor thus uncovers an unique tumor differentiation trajectory, where immature and mature neutrophils converge into a terminally differentiated tumor neutrophil state.
2024-01-11 | GSE243466 | GEO
Project description:Despite the remarkable success of immunotherapy, only ~20-30% of cancer patients display an extended durable response. Pre-existing biomarkers for immunotherapy outcome are significantly limited in their predictive power. While mice are the most widely used and cost-effective model to study human disease, translating preclinical biomarkers into clinical practice faces significant obstacles – in part due to the lack of diverse or appropriate models. Here, to improve translatability and identify novel biomarkers, we showcase an approach encompassing several pre-clinical models - each capturing one possible mechanistic aspect of immunotherapy response, such as tumor- and host-dependency, in order to reflect the variability seen in human cancers. Using this approach, we identify interferon-stimulated, Ly6Ehi neutrophils as a pre-treatment, blood-borne biomarker for anti-PD1 response in mice. We subsequently validate this result in cohorts of immunotherapy-treated non-small cell lung cancer (NSCLC) and melanoma patients, where the abundance of Ly6Ehi neutrophils predicts anti-PD1 response and further validated these results using available datasets for other cancers. Moreover, we demonstrate that these cells sensitize otherwise resistant tumors to anti-PD1 therapy, in part by directly activating cytotoxic T cells and contributing to tumor cell killing, while operate upstream of T cells in the immunotherapy response. Collectively, our study identifies a new and functionally active biomarker to predict immunotherapy outcome with potential clinical relevance.
2024-01-05 | GSE226962 | GEO