Antitumor T-cell Homeostatic Activation Is Uncoupled from Homeostatic Inhibition by Checkpoint Blockade

Abstract

T-cell transfer into lymphodepleted recipients induces homeostatic activation and potentiates antitumor efficacy. In contrast to canonical TCR-induced activation, homeostatic activation yields a distinct phenotype and memory state whose regulatory mechanisms are poorly understood. Here, we show in patients and murine models that, following transfer into lymphodepleted bone marrow transplant (BMT) recipients, CD8 + T-cells undergo activation but also simultaneous homeostatic inhibition manifest in upregulation of immune checkpoint molecules and functional suppression. T-cell transferred into BMT recipients were protected from homeostatic inhibition by PD1/CTLA4 dual checkpoint blockade (dCB). This combination of dCB and BMT-'immunotransplant'increased T-cell homeostatic activation and anti-tumor T-cell responses by an order of magnitude. Like homeostatic activation, homeostatic inhibition is IL-7/IL-15-dependent, revealing mechanistic coupling of these two processes. Marked similarity in ex vivo modulation of post-BMT T-cell in mice and patients is promising for the clinical translation of immunotransplant (NCT03305445) and for addressing homeostatic inhibition in T-cell therapies.

Human Vaccines & Immunotherapeutics: news

“…Bone marrow transplant combined with checkpoint blockade might work for lymphoma Durable responses in lymphoma and solid tumor models were reported after hematopoietic stem cell transplantation and dual PD-1/CTLA-4 checkpoint blockade immunotherapy. 4 T-cell transfer into lymphodepleted patients activates cellular antitumor immunity, but often leads to induction of the checkpoint surface receptors. Their simultaneous targeting increased the responses in both human and mouse subjects.…”

Expression of PD-1 and TIM-3 inhibitory checkpoint molecules by T-lymphocytes in early post-transplant period in multiple myeloma patients

“…В работах N. Marshall и соавт. [14] и F. Simonetta и соавт. [16], исследовавших уровень экспрессии PD-1 после ауто- ТГСК и трансплантации аллогенных гемопоэтических стволовых клеток, соответственно, также было показано неожиданное увеличение экспрессии PD-1 и относительного содержания PD-1 + Т-клеток после выхода из лейкопении.…”

“…Динамика восстановления Т-клеток, экспрессирующих ИСМ, после ауто-ТГСК, в том числе при ММ, недостаточно изучена, а имеющиеся данные противоречивы. Увеличение экспрессии PD-1 описано в последние два года в моделях трансплантации гемопоэтических стволовых клеток, выполненных на мышах [14,15], у больных после ауто-ТГСК [14], у больных гемобластозами после трансплантации аллогенных гемопоэтических стволовых клеток [16] и больных системной склеродермией после ауто-ТГСК [17]. У больных ММ не было ранее выявлено различий в содержании ИСМ до и после ВХТ с ауто-ТГСК [18].…”

Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial

“…It was recently reported that CD8 + T cells undergo activation and homeostatic inhibition manifested by up-regulation of PD1, resulting in functional suppression. The addition of checkpoint blockade, including anti-PD1 therapy, prevented homeostatic inhibition and improved antitumor T cell responses in murine preclinical models ( Marshall et al, 2019 ). Collectively, these data suggest that the addition of a PD1-blocking checkpoint antibody to the vaccine maneuver might improve the immune response rate and subsequent therapeutic effects.…”