التفاصيل البيبلوغرافية
| العنوان: |
Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function. |
| المؤلفون: |
Salter, Alexander I., Rajan, Anusha, Kennedy, Jacob J., Ivey, Richard G., Shelby, Sarah A., Leung, Isabel, Templeton, Megan L., Muhunthan, Vishaka, Voillet, Valentin, Sommermeyer, Daniel, Whiteaker, Jeffrey R., Gottardo, Raphael, Veatch, Sarah L., Paulovich, Amanda G., Riddell, Stanley R. |
| المصدر: |
Science Signaling; 8/24/2021, Vol. 14 Issue 697, p1-17, 17p |
| مصطلحات موضوعية: |
T cells, CD19 antigen, CHIMERIC antigen receptors, AUTOMOBILES, T cell receptors, TUMOR antigens, BREAST cancer |
| مستخلص: |
Stepping up CAR T cell sensitivity: Chimeric antigen receptors (CARs) were designed to mimic activated endogenous T cell receptors (TCRs) and induce a cytotoxic response to tumor antigen. However, CARs require more antigen than TCRs for activation, thereby causing treatment exclusion or failure and relapse in many patients. To design CARs with a lower activation threshold, Salter et al. compared antigen-induced pathway signaling in human T cells expressing a current CAR construct to that in cells with endogenous TCRs. The analysis informed the design of new CARs that more robustly activated a T cell co-receptor and an adaptor, resulting in CAR T cells that more effectively responded to low antigen density tumor cells in culture and decreased tumor burden and mortality in mice. Chimeric antigen receptor (CAR)–modified T cell therapy is effective in treating lymphomas, leukemias, and multiple myeloma in which the tumor cells express high amounts of target antigen. However, achieving durable remission for these hematological malignancies and extending CAR T cell therapy to patients with solid tumors will require receptors that can recognize and eliminate tumor cells with a low density of target antigen. Although CARs were designed to mimic T cell receptor (TCR) signaling, TCRs are at least 100-fold more sensitive to antigen. To design a CAR with improved antigen sensitivity, we directly compared TCR and CAR signaling in primary human T cells. Global phosphoproteomic analysis revealed that key T cell signaling proteins—such as CD3δ, CD3ε, and CD3γ, which comprise a portion of the T cell co-receptor, as well as the TCR adaptor protein LAT—were either not phosphorylated or were only weakly phosphorylated by CAR stimulation. Modifying a commonplace 4-1BB/CD3ζ CAR sequence to better engage CD3ε and LAT using embedded CD3ε or GRB2 domains resulted in enhanced T cell activation in vitro in settings of a low density of antigen, and improved efficacy in in vivo models of lymphoma, leukemia, and breast cancer. These CARs represent examples of alterations in receptor design that were guided by in-depth interrogation of T cell signaling. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
