Inclusion of Dap10 or 4-1BB costimulation domains in the chPD1 receptor enhances anti-tumor efficacy of T cells in murine models of lymphoma and melanoma. 2020

Hailey Kintz, and Emily Nylen, and Amorette Barber
Department of Biological and Environmental Sciences, Longwood University, Farmville, VA, USA.

Chimeric antigen receptors (CAR) utilize costimulatory domains to enhance anti-tumor efficacy. However, it is unclear which costimulatory domain is preferable. Therefore, the intracellular domains of CD28, Dap10, 41BB, GITR, ICOS, or OX40 were compared in a murine chimeric PD1 (chPD1) receptor that targets tumor-associated PD1 ligands. Upon antigen restimulation, T cells expressing chPD1-CD28 receptors had reduced lytic capacity. While most of the chPD1 T cell receptors secreted pro-inflammatory (IFNγ, TNFα, IL-2, GM-CSF, IL-17, and IL-21) and anti-inflammatory cytokines (IL-10), chPD1-Dap10 did not secrete IL-10. Furthermore, chPD1-Dap10 and -41BB receptors induced a memory precursor phenotype, had enhanced persistence in vivo, and superior therapeutic efficacy in murine models of T cell lymphoma and melanoma compared to chPD1-CD28 or chPD1-GITR expressing T cells. Therefore, each costimulatory domain induces differential effects in CAR-expressing T cells and inclusion of Dap10 or 4-1BB costimulatory domains may induce a preferential cytokine profile and differentiation for cancer therapy.

UI MeSH Term Description Entries
D008223 Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Germinoblastoma,Lymphoma, Malignant,Reticulolymphosarcoma,Sarcoma, Germinoblastic,Germinoblastic Sarcoma,Germinoblastic Sarcomas,Germinoblastomas,Lymphomas,Lymphomas, Malignant,Malignant Lymphoma,Malignant Lymphomas,Reticulolymphosarcomas,Sarcomas, Germinoblastic
D008297 Male Males
D008546 Melanoma, Experimental Experimentally induced tumor that produces MELANIN in animals to provide a model for studying human MELANOMA. B16 Melanoma,Melanoma, B16,Melanoma, Cloudman S91,Melanoma, Harding-Passey,Experimental Melanoma,Experimental Melanomas,Harding Passey Melanoma,Melanomas, Experimental,B16 Melanomas,Cloudman S91 Melanoma,Harding-Passey Melanoma,Melanoma, Harding Passey,Melanomas, B16,S91 Melanoma, Cloudman
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D011948 Receptors, Antigen, T-Cell Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens (CD3 COMPLEX). Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta (RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA) or gamma-delta (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA) chains. Antigen Receptors, T-Cell,T-Cell Receptors,Receptors, T-Cell Antigen,T-Cell Antigen Receptor,T-Cell Receptor,Antigen Receptor, T-Cell,Antigen Receptors, T Cell,Receptor, T-Cell,Receptor, T-Cell Antigen,Receptors, T Cell Antigen,Receptors, T-Cell,T Cell Antigen Receptor,T Cell Receptor,T Cell Receptors,T-Cell Antigen Receptors
D011971 Receptors, Immunologic Cell surface molecules on cells of the immune system that specifically bind surface molecules or messenger molecules and trigger changes in the behavior of cells. Although these receptors were first identified in the immune system, many have important functions elsewhere. Immunologic Receptors,Immunologic Receptor,Immunological Receptors,Receptor, Immunologic,Receptors, Immunological
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005260 Female Females
D000076962 Receptors, Chimeric Antigen Synthetic cellular receptors that reprogram T-LYMPHOCYTES to selectively bind antigens. Chimeric Antigen Receptor,Chimeric T-Cell Receptor,Artificial T-Cell Receptors,Chimeric Antigen Receptors,Chimeric Immunoreceptors,Chimeric T-Cell Receptors,Antigen Receptor, Chimeric,Antigen Receptors, Chimeric,Artificial T Cell Receptors,Chimeric T Cell Receptor,Chimeric T Cell Receptors,Immunoreceptors, Chimeric,Receptor, Chimeric Antigen,Receptor, Chimeric T-Cell,Receptors, Artificial T-Cell,Receptors, Chimeric T-Cell,T-Cell Receptor, Chimeric,T-Cell Receptors, Artificial,T-Cell Receptors, Chimeric
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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