Selected biological issues affecting relapse after stem cell transplantation: role of T-cell impairment, NK cells and intrinsic tumor resistance

Abstract

The graft vs. leukemia (GvL) effect as a method of preventing relapse is well described after allogeneic hematopoietic cell transplantation (HCT), but the mechanisms to this effect and how tumor sometimes develops resistance to GvL are just beginning to be understood. This article reviews and expands upon data presented at the Third International Workshop on Biology, Prevention and Treatment of Relapse after Stem Cell Transplantation held in Hamburg, Germany, in November 2016. We first discuss in detail the role that T-cell impairment early after HCT plays in relapse by looking at data from T cell-depleted approaches as well as the clear role that early T-cell recovery has shown in improving outcomes. We then review key findings regarding the role of specific KIR donor/recipient pairings that contribute to relapse prevention after HCT for several tumor types. Finally, we discuss a unique mouse model following the development of tumor resistance to GvL. Detailed molecular characterization of events marking the development of tumor resistance to the immunotherapy of GvL may help in developing future strategies to overcome immune escape.

Attenuation of apoptotic cell detection triggers thymic regeneration after damage

“…Of note, the general phenomena of endogenous thymic regeneration has been known for longer even than its immunological function ( Jaffe, 1924 ; Miller, 1961 ); however, the underlying mechanisms controlling this process are poorly understood ( Chidgey et al, 2007 ; Dudakov et al, 2010 ). Thus, endogenous thymic regeneration is a critical process to restore immune competence following thymic injury, although acute and profound thymic damage such as that caused by common cancer cytoreductive therapies, conditioning regimes as part of hematopoietic cell transplantation (HCT), or age-related thymic involution lead to prolonged T cell deficiency, precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse ( Bosch et al, 2012 ; Clave et al, 2013 ; Dudakov et al, 2016 ; Komanduri et al, 2007 ; Legrand et al, 2007 ; Mackall, 2000 ; Mackall et al, 1995 ; Parkman and Weinberg, 1997 ; Pizzo et al, 1991 ; van den Brink et al, 2018 ; Weinberg et al, 1995 ; Williams et al, 2007 ). Recent studies have shown that thymic ILCs and ECs have profound reparative effects in the thymus after acute injury through their production of the regeneration-associated factors IL-22 and BMP4, respectively, both of which act by stimulating TECs ( Dudakov et al, 2012 , 2017 ; Wertheimer et al, 2018 ).…”

Attenuation of homeostatic signaling from apoptotic thymocytes triggers a global regenerative response in the thymus

“…Thus, endogenous thymic regeneration is a critical process to restore immune competence following thymic injury. Although there is likely continual thymic involution and regeneration in response to stress and infection in otherwise healthy people, acute and profound thymic damage such as that caused by common cancer cytoreductive therapies, conditioning regimes as part of hematopoietic cell transplantation (HCT), or age-related thymic involution, leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse 8,9,[57][58][59][60][61][62][63][64][65][66] . Of note, the general phenomena of endogenous thymic regeneration has been known for longer even than its immunological function 67,68 , however, the underlying mechanisms controlling this process have been largely unstudied 6,69 .…”

“…However, the thymus is exceptionally sensitive to negative stimuli that, together with its well-characterized capacity for repair, leads to continual cycles of involution and regeneration in response to acute injury [3][4][5] . However, this capacity for regeneration declines with age as a function of thymic involution, which itself leads to a reduced capacity to respond to new pathogens, as well as poor response to vaccines and immunotherapy [6][7][8][9] . Therefore, there is a pressing clinical need for the development of therapeutic strategies that can enhance T cell reconstitution.…”

Biogenic Zinc Oxide Nanoparticles Attenuate Acute Lymphoblastic Leukemia Cell Proliferation through Oxidative Stress and DNA Damage

“…On the other hand, other T-cell leukemia have 5-25% bone marrow contribution, which is much lower than that of T-ALL. 3,4 Irrespective of different T-ALL origins, the treatment method is coordinated with other T-cell leukemia such as T-LBL. Different modes of treatment such as radiation, stem cell transplantation, etc, in T-ALL, show better outcomes, but relapse patients' cure rates are lower than 30%, 5 and outcomes for relapsed T-LBL are even worse.…”