Methods and compositions for natural killer cells
Disclosed herein are novel compositions and methods for stimulation of and the production or expansion of natural killer (NK) cells. Numbers of NK cells can be increased following contact with exosomes modified with one or more stimulatory peptides. Methods and compositions for the production of exosomes, wherein the exosomes comprises stimulatory peptides are also described. Also described are methods of treating cancer using the disclosed NK-stimulating exosomes or NK cells stimulated by the disclosed methods.
1. A composition comprising engineered NK cell stimulating exosomes each comprising a membrane, and at least two stimulatory peptides comprising 4-1BB ligand (4-1BBL) and interleukin-21 (IL-21), each stimulatory peptide embedded in an exosome membrane, wherein each exosome is an extracellular product of the engineered exosomal secretory cell line K562-mb21-41BBL.
2. The composition of claim 1 , further comprising at least one stimulatory peptide selected from the group consisting of, interleukin-2 (IL-2), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), Major histocompatibility complex class 1-related chain A/B (MICA A/B), UL16 Binding Protein 2 (ULBP2), Intracellular adhesion molecule-1 (ICAM-1), 2B4, B Cell Membrane protein 1/signaling lymphocyte activation molecule (SLAM) family member 2 (F2) (BCM1/SLAMF2), cluster of differentiation 155 (CD155), cluster of differentiation 112 (CD112), C-C chemokine receptor type 7 (CCR7), DnaX activation protein of 12 kDa (DAP12), and DnaX activation protein of 10 kDa (DAP10).
3. The composition of claim 1 , wherein one or more of the stimulatory peptides are coupled to a membrane-inserting peptide.
4. The composition of claim 3 , wherein the membrane-inserting peptide comprises a segment of CD4, IgG, or a combination thereof, with affinity for a lipid bilayer.
5. The composition of claim 3 , wherein the one or more stimulatory peptides coupled to a membrane-inserting peptide is a fusion protein.
6. The composition of claim 3 , wherein the membrane-inserting peptide comprises human fragment crystallizable region (Fc), Glvcosylphosphatidvlinositol (GPI), trans-membrane T-cell receptor, or pH low insertion peptide (pHLIP).
7. The composition of claim 1 , further comprising a pharmaceutical carrier.