Physical Resistance to Immune Cell Attack by the Cellular Glycocalyx

Document text

Principal Investigator: Matthew J Paszek
Organization: CORNELL UNIVERSITY
Fiscal Year: 2024
Award: $428,910
Funding agency: National Cancer Institute

Project Summary/Abstract
Cancer cells construct a cellular glycocalyx with biochemical and biophysical attributes that protect against attack
by effector immune cells. Currently, our mechanistic understanding of how the cancer-cell glycocalyx may
physically interfere with any of the multiple pathways and individual steps of effector-cell mediated killing is highly
limited. Our overarching hypothesis is that by developing a better physical understanding of the glycocalyx in
resistance to immune cell attack, we can better devise new cellular engineering strategies to overcome the
glycocalyx barrier. Our project will specifically focus on glycocalyx-mediated protection against attack by Natural
Killer (NK) cells, which are attracting significant attention in the field of cancer immunotherapy. NK cells possess
natural cytotoxic activity against tumor cells and can be further engineered with a chimeric antigen receptor
(CAR) to target a specific tumor antigen. As such, NK cells are exciting candidates for adoptive cell therapy. Cell
surface mucins are highly overexpressed in cancer and serve as primary structural elements of the glycocalyx.
In this proposal, our aims are to (1) determine how specific molecular properties of mucins govern the glycocalyx
structure and thereby mediate cellular resistance to NK-cell attack; (2) identify the specific mechanisms through
which mucins physically disrupt NK and CAR-NK attack; and (3) develop NK cellular engineering strategies to
overcome the mucin barrier.
To complete our aims, we will employ state-of-the-art imaging approaches that our lab has developed for
characterizing the nanoscale material structure of the glycocalyx. We also will take advantage of our lab’s
expertise and validated tools for engineering the physical structure of the glycocalyx. Combining these imaging
and cellular engineering strategies with established techniques in immune cell biology will enable new specific
hypotheses regarding the physical functioning of the glycocalyx in protection against immune cell attack to be
tested. They will also support the design and testing of engineered NK cells with structure-optimized CARs and
glycocalyx-editing enzymes for improved elimination of mucin-bearing cancer cells.
Adoptive cell therapy has tremendous promise for treating otherwise recalcitrant cancers. In part due to the
technical challenges of manipulating and characterizing the physical structure of the glycocalyx, our physical
understanding of the cancer-cell glycocalyx in resistance to adoptive cell therapy is poor. Our project will address
this knowledge gap and test new strategies for NK engineering that, if successful, can be further developed for
clinical applications.

Terms: <Adoptive Cell Transfers><Attention><Biochemical><Biocompatible Coated Materials><Biophysics><Biopolymers><CAR NK><Cancer Treatment><Cancers><Cations><Cell Body><Cell Coat><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell surface><Cell-to-Cell Interaction><Cells><Cellular biology><Cessation of life><Clinical><Cytolysis><Cytoplasmic Granules><Cytotoxic cell><Death><Detection><Development><Dimensions><Ecologic Monitoring><Ecological Monitoring><Effector Cell><Elements><Endowment><Engineering><Environmental Monitoring><Enzyme Gene><Enzymes><Glycans><Glycocalyx><Goals><Human><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune><Immune Evasion><Immune destruction><Immune mediated destruction><Immune mediated therapy><Immune system><Immunes><Immunologically Directed Therapy><Immunotherapy><Individual><Interference Microscopy><Intracellular Communication and Signaling><Intrinsic factor><K lymphocyte><Knowledge><Lysis><Lytotoxicity><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Metabolic><Metabolic Glycosylation><Microinterferometry><Microscopic Interferometry><Microvilli><Microvillus><Modern Man><Molecular><Mucins><Mucolytic Agents><Mucolytics><Mucus Glycoprotein><NK Cells><Natural Killer Cells><Oncogenic><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Pattern><Penetration><Physical Function><Polymers><Polysaccharides><Predisposition><Process><Property><Receptor Protein><Receptor Signaling><Refractory><Reporter><Reporting><Resistance><Role><Scanning><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Surface><Surface-Coated Materials><Susceptibility><Techniques><Technology><Testing><Therapeutic><Thick><Thickness><Tumor Antigens><Tumor Cell><Tumor-Associated Antigen><adoptive cell therapy><adoptive cellular therapy><anti-cancer immunotherapy><anti-cancer therapy><anticancer immunotherapy><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><cancer antigens><cancer cell><cancer immunotherapy><cancer therapy><cancer-directed therapy><cell biology><cell engineering><cell killing><cell type><cellular engineering><cellular microvillus><chimeric antigen receptor><chimeric antigen receptor engineered natural killer cell><chimeric antigen receptor natural killer cells><clinical applicability><clinical application><clinical relevance><clinically relevant><coated materials><cytotoxic><cytotoxicity><design><designing><developmental><engineered NK cell><engineered immune system><engineered natural killer cell><environmental testing><extracellular><glycosylation><granule><imaging><imaging approach><imaging based approach><immune engineering><immune evasive><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><immunoengineering><immunotherapy for cancer><immunotherapy of cancer><improved><innovate><innovation><innovative><insight><interest><malignancy><mucinase><nano meter scale><nano meter sized><nanometer><nanometer scale><nanometer sized><nanoscale><natural killer cells expressing chimeric antigen receptors><natural killer cells with chimeric antigen receptors><neoplasm/cancer><neoplastic cell><overexpress><overexpression><pathway><patient oriented outcomes><physical property><polymer><polymeric><programs><receptor><resistant><social role><superresolution imaging><tool><tumor-specific antigen><uptake>