T-cell Exhaustion in XXXX after Autotransplant: Optimal Timing of Immunotherapy.

@entity1 @entity1619 @entity404 @entity20500 @entity20867 @entity1361 @entity4755 @entity1582 @entity6985 @entity8395 @entity405 @entity4386
UNASSIGNED: @entity1582 is the most common indication for high-dose chemotherapy and autologous stem cell transplantation (ASCT), and @entity6985 maintenance after transplant is now standard. Although @entity6985 doubles progression-free survival, almost all @entity1 eventually relapse. Posttransplant immunotherapy to improve outcomes after ASCT therefore has great merit but first requires delineation of the dynamics of immune reconstitution. We evaluated lymphocyte composition and function after ASCT to guide optimal timing of immunotherapy and to identify potential markers of relapse. @entity1619 cells (Treg) decline as @entity405 (+) T cells expand during early lymphocyte recovery after ASCT, markedly reducing the Treg: @entity405 (+) effector T-cell ratio. These @entity405 (+) T cells can respond to autologous dendritic cells presenting tumor antigen in vitro as early as day +12 after transplant, becoming antigen-specific cytolytic T-lymphocyte effectors and thereby demonstrating preservation of cellular reactivity. @entity404 (+) and @entity405 (+) T cells express the negative regulatory molecules, @entity4386 , @entity8395 , @entity20867 , and @entity20500 , before and after ASCT. A subpopulation of exhausted/senescent @entity405 (+) T cells, however, downregulates @entity1361 and upregulates @entity4755 and @entity8395 , characterizing immune impairment and relapse after ASCT. Relapsing @entity1 have higher numbers of these cells at +3 months after transplant, but before detection of clinical disease, indicating their applicability in identifying @entity1 at higher risk of relapse. @entity8395 blockade also revives the proliferation and cytokine secretion of the hyporesponsive, exhausted/senescent @entity405 (+) T cells in vitro. Collectively, these results identify T-cell exhaustion/senescence as a distinguishing feature of relapse and support early introduction of immunotherapy to stimulate antitumor immunity after ASCT. Cancer Immunol Res; 4(1); 1-11.   2015 AACR.
