Investigating the Ability of Human Blood Neutrophils to Kill Cancer

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Jonathan S Reichner
Organization: RHODE ISLAND HOSPITAL
Fiscal Year: 2024
Award: $82,000
Funding agency: National Cancer Institute

Abstract
Neutrophils are not often considered as cancer killing immune cells in the same way that natural killer cells,
cytotoxic T cells and macrophages. However, the inherent capability of neutrophils to be cytotoxic is clinically
evident in diseases of hyperinflammation (such as sepsis) where activated neutrophils contribute to organ failure
by destroying otherwise healthy cells and tissues. Therefore, neutrophils possess all the cytolytic machinery
needed to be destructive to host tissues and we propose that includes cancer. What is lacking is a clearly defined
targeting mechanism that can focus the cytotoxic potential of neutrophils towards cancer cells in a specific and
controlled manner. This proposal will present published and preliminary evidence that neutrophils can indeed
be successfully targeted to cancer cells leading to a newly described non-apoptotic cancer killing mechanism
called trogoptosis. Trogoptosis (Greek: trogo; “gnaw”) is a newly described effector mechanism that brings
neutrophils into the discussion of tumor killing immune cells. Trogoptosis is a form of antibody-dependent cellular
cytotoxicity (ADCC) that triggers neutrophils to destroy antibody-opsonized tumor targets by forming a transient
receptor-mediated synapse between the neutrophil and the tumor target. Killing occurs as a result of the
neutrophil gnawing at the tumor plasma membrane and dismembering it into chunks, and is distinct from
apoptosis and necrosis. Neutrophils internalize these pieces of tumor cells by phagocytosis and migrate away.
Trogoptosis is dependent on the neutrophil beta2 integrin Complement Receptor 3 (CR3; CD11b/CD18; Mac-1).
Antibody blockade of CR3, or neutrophils from families with genetic absence of CR3, obviate trogoptosis. Given
the relative recency of this discovery, there remains much to be learned about this effector mechanism.
 A highly selected experimental plan is offered to fit within the budget and timeframe of an R03 yet allow
rigorous testing of the hypothesis that neutrophil trogoptosis is a function that can be enhanced by agonists of
neutrophil CR3 and augment the efficacy of anti-cancer antibody therapy. This R03 would develop a nascent
collaboration between two laboratories with a track record in the use of biomimetic experimental systems to
study breast cancer invasion and the function of human neutrophils. The experimental approach will use fibrous
gels of varying stiffnesses and ECM composition that reflect differences that exist among various bodily tissues
and organs. MDA-231 TNBC will be modeled as single invasive cells (Specific Aim 1) and as 3D spheroids
(Specific Aim 2) in testing the trogoptoptic killing by human neutrophils introduced as tumoricidal effector cells.
Additional work will determine if neutrophil CR3 is a druggable target that can enhance the effectiveness of
neutrophil-dependent tumor killing and thereby potentially serve as an adjuvant to anti-tumor antibody therapy
in the clinic. Our overall objective is to demonstrate that human neutrophils can be stimulated to function
effectively and specifically as tumoricidal immune cells.

Terms: <3-D><3-Dimensional><3D><3D cell culture><3D culture><Ab-dependent cellular cytotoxicity><Adherent Culture><Adhesions><Adjuvant><Adjuvant Chemotherapy><Adjuvant Drug Therapy><Agonist><Antibodies><Antibody Therapy><Antitumor Response><Apoptosis><Apoptosis Pathway><Beta 2 Integrin Chain><Biological Mimetics><Biomimetics><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Body Tissues><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Tumor Patient><Budgets><CD11a Beta Subunit><CD11b><CD11b Beta Subunit><CD11c Beta Subunit><CD18><CD18 Antigens><CR3><CR3 Receptor><CR3A><Cancers><Cell Body><Cell membrane><Cell surface><Cell-Extracellular Matrix><Cell-Mediated Lympholytic Cells><Cells><Cellular Spheroids><Cessation of life><Clinic><Clinical><Collaborations><Complement><Complement 3 Receptor><Complement Proteins><Cytolytic T-Cell><Cytoplasmic Membrane><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Cytotoxic cell><Data><Death><Disease><Disorder><ECM><EGF Receptor><EGFR><ERBB Protein><Effectiveness><Effector Cell><Elasticity><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Exhibits><Extracellular Matrix><Family><Fibroblasts><Fibroins><Gel><Genetic><Greek><HER1><Host Defense><Human><ITGAM><ITGAM gene><ITGB2><ITGB2 gene><Immune><Immune mediated therapy><Immune response><Immunes><Immunological response><Immunologically Directed Therapy><Immunotherapy><Infection><Integrin Beta-2><Integrin alpha-M beta-2><Integrin alphaMbeta2><Integrin beta2><Integrins><Integrins Extracellular Matrix><Invaded><K lymphocyte><LCAMB><Laboratories><Learning><Lectin><MAC1A><MDA MB 231><MDA-231><MDA-MB231><MF17><MO1A><Mac 1><Mac-1 Adhesive Receptor><Mac-1 Antigen><Mac-1 Receptor><Macrophage><Macrophage-1 Antigen><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Mediating><Medical><Mo1 Antigen Receptor><Mo1 Glycoprotein Receptor><Modeling><Modern Man><Monolayer culture><Multicellular Spheroids><Mφ><NK Cells><Natural Killer Cells><Necrosis><Necrotic><Neoplasm Antibodies><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Granulocyte><Neutrophilic Infiltrate><Neutrophilic Leukocyte><Organ><Organ failure><Phagocytosis><Physiologic><Physiological><Plasma Membrane><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Programmed Cell Death><Protocol><Protocols documentation><Psychological reinforcement><Publishing><Puncture procedure><Punctures><Receptor Protein><Regulatory Element><Reinforcement><Sepsis><Silk><Site><Structure><Synapses><Synaptic><System><TGF-alpha Receptor><TNBC><Testing><Therapeutic><Tissues><Transforming Growth Factor alpha Receptor><Tumor Antibodies><Tumor Cell><Urogastrone Receptor><Work><anti-cancer><anti-cancer immunotherapy><anti-tumor antibody><anti-tumor response><antibody based therapies><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody mediated cellular cytotoxicity><antibody treatment><antibody-based therapeutics><antibody-based treatment><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><anticancer immunotherapy><antitumor antibody><blood infection><bloodstream infection><breast tumor cell><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer immunotherapy><cancer progression><cell killing><clinical relevance><clinically relevant><complementation><cytotoxic><determine efficacy><druggable target><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><host response><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><insight><interest><killer T cell><live cell image><live cell imaging><live cellular image><live cellular imaging><malignancy><malignant breast tumor><migration><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><neutrophil><physical property><plasmalemma><proto-oncogene protein c-erbB-1><receptor><spheroids><synapse><three dimensional><three dimensional cell culture><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor progression><αMβ2>