Th169 - Detection and Clonal Dynamics of Alloreactive T Cells in a Kidney Transplant Recipient Experiencing Acute Rejection After Immune Checkpoint Inhibitor Therapy

Abstract Text: Immune checkpoint inhibitors (ICI) have been established as an effective standard care for many cancers, though it is often complicated by immune-related adverse events. Kidney transplant recipients have 3-10x higher risk of cancer post-transplantation, but the use of ICI is challenging due to the high risk of acute allograft rejection. We hypothesized that this could be explained by a vigorous and rapid expansion of preexisting, allograft-specific memory T cells after the initiation of ICI therapy. Here we leveraged a unique set of tissue and blood samples from a patient who experienced kidney allograft rejection during ICI therapy. To first identify these alloreactive cells, we performed a mixed lymphocyte reaction (MLR) using recipient PBMCs and donor splenocytes. Proliferating recipient T cells were flow-sorted and paired single-cell RNA and TCR sequencing was performed. We observed a population of highly proliferative and clonally expanded CD8+ T cells, which we posited to be alloreactive clones. When examining the presence of MLR-identified clones in bulk TCR sequencing of tissue samples, we found these alloreactive clones in the rejected kidney but not in lymph node or skin biopsies. Similarly, examination of a PBMC time-course showed these alloreactive clones could not be detected before ICI initiation but were found in high numbers after therapy initiation. Combined, this work describes the identification and spatiotemporal dynamics of a set of alloreactive T cells in a patient experiencing acute rejection after ICI therapy and highlights the utility of this technique to track pathologic T cell responses augmented by ICI therapy.