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Supplementary Figures 1 - 6 from Durable Adoptive Immunotherapy for Leukemia Produced by Manipulation of Multiple Regulatory Pathways of CD8+ T-Cell Tolerance

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posted on 2023-03-30, 22:06 authored by Melissa M. Berrien-Elliott, Stephanie R. Jackson, Jennifer M. Meyer, Craig J. Rouskey, Thanh-Long M. Nguyen, Hideo Yagita, Philip D. Greenberg, Richard J. DiPaolo, Ryan M. Teague

PDF file - 643K, Supplementary Figure S1. Surface expression of co-stimulatory and co-inhibitory molecules on FBL tumor cells. Supplementary Figure S2. Transferred T cells are deleted via apoptosis. Supplementary Figure S3. Survival of transferred T cells is not sufficient for acquisition of effector function. Supplementary Figure S4. Systemic inflammation and provision of high-dose IL-2 fail to prevent deletion of adoptively transferred CD8+ T cells. Supplementary Figure S5. LAG3 blockade has limited additional impact on survival of transferred T cells. Supplementary Figure S6. LAG3 blockade combines with PD-1/CTLA4 blockade to promote expansion and effector function by transferred T cells.

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ARTICLE ABSTRACT

Tolerizing mechanisms within the host and tumor microenvironment inhibit T-cell effector functions that can control cancer. These mechanisms blunt adoptive immunotherapy with infused T-cells due to a complex array of signals that determine T-cell tolerance, survival, or deletion. Ligation of the negative regulatory receptors CTLA4, PD-1(PDCD1), or LAG3 on T-cells normally hinders their response to antigen through nonredundant biochemical processes that interfere with stimulatory pathways. In this study, we used an established mouse model of T-cell tolerance to define the roles of these inhibitory receptors in regulating CD8+ T-cell tolerance during adoptive immunotherapy to treat leukemia. Blocking CTLA4 and PD-1 in vivo combined to promote survival of transferred T-cells despite powerful deletional signals that mediate Bim (BCL2L11)–dependent apoptosis. However, this dual blockade was not optimal for stimulating effector function by responding T-cells, which required the additional blockade of LAG3 to induce full expansion and allow the acquisition of robust cytolytic activity. Thus, the cooperation of multiple distinct regulatory pathways was needed for the survival and effector differentiation of adoptively transferred tumor-reactive CD8+ T-cells. Our work defines the immune escape pathways in which simultaneous blockade could yield durable immunotherapeutic responses that can eradicate disseminated leukemia. Cancer Res; 73(2); 605–16. ©2012 AACR.

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