This prospective longitudinal study examined and compared two measures (prospective and retrospective ones) of post-traumatic growth (PTG) following Hematopoietic Stem-Cell Transplantation (HSCT) and their respective relationships with mental health and psychological disposition. We also tested the hypothesis that unwillingness to be in contact with distressing thoughts and feelings-i.e. experiential avoidance-would moderate the relationship between Post-Traumatic Stress Disorder (PTSD) and growth.

CD19 chimeric antigen receptor (CAR) T cells can induce prolonged remissions and potentially cure a significant proportion of patients with relapsed/refractory large B-cell lymphomas. However, some patients may die of causes unrelated to lymphoma after CAR T-cell therapy. To date, little is known about the nonrelapse mortality (NRM) after CAR T-cell therapy. Using the French DESCAR-T registry, we analyzed the incidence and causes of NRM and identified risk factors of NRM. We report on 957 patients who received standard-of-care axicabtagene ciloleucel (n = 598) or tisagenlecleucel (n = 359) between July 2018 and April 2022, in 27 French centers. With a median follow-up of 12.4 months, overall NRM occurred in 48 patients (5.0% of all patients): early (before day 28 after infusion) in 9 patients (0.9% of all patients and 19% of overall NRM), and late (on/after day 28 after infusion) in 39 patients (4.1% of all patients and 81% of overall NRM). Causes of overall NRM were distributed as follows: 56% infections (29% with non-COVID-19 and 27% with COVID-19), 10% cytokine release syndromes, 6% stroke, 6% cerebral hemorrhage, 6% second malignancies, 4% immune effector cell associated neurotoxicities, and 10% deaths from other causes. We report risk factors of early NRM and overall NRM. In multivariate analysis, both diabetes and elevated ferritin level at lymphodepletion were associated with an increased risk of overall NRM. Our results may help physicians in patient selection and management in order to reduce the NRM after CAR T-cell therapy.

Achieving complete remission (CR) is the main goal in AML treatment and a prerequisite for successful autologous stem cell transplantation (ACT).

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.

Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) is routinely performed with peripheral blood stem cells (PBSCs) mobilized by injection of G-CSF, a growth factor which not only modulates normal hematopoiesis but also induces diverse immature regulatory cells. Based on our previous evidence that G-CSF-mobilized multipotent hematopoietic progenitors (MPP) can increase survival and proliferation of natural regulatory T cells (Tregs) in autoimmune disorders, we addressed the question how these cells come into play in mice and humans in an alloimmune setting. Using a C57BL/6 mouse model, we demonstrate that mobilized MPP enhance the immunosuppressant effect exerted by Tregs, against alloreactive T lymphocytes, both in vitro and in vivo. They do so by migrating to sites of allopriming, interacting with donor Tregs and increasing their numbers, thus reducing the lethality of graft-versus-host disease (GVHD). Protection correlates likewise with increased allospecific Treg counts. Furthermore, we provide evidence for a phenotypically similar MPP population in humans, where it shares the capacity to promote selective Treg expansion in vitro. We postulate that G-CSF-mobilized MPPs might become a valuable cellular therapy to expand donor Tregs in vivo and prevent GVHD, thereby making allo-HSCT safer for the treatment of leukemia patients.

Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c(+) DCs engineered to express a high-affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated. We found that depletion of CD11c(+) cells from CD11c.DTR mice induced the expansion of a variant CD64(+) Ly6C(+) monocyte population in the spleen and blood that was distinct from conventional monocytes. Expansion of CD64(+) Ly6C(+) monocytes was independent of mobilization from the BM via CCR2 but required the cytokine, G-CSF. Indeed, this population was also expanded upon exposure to exogenous G-CSF in the absence of DC depletion. CD64(+) Ly6C(+) monocytes were characterized by upregulation of innate signaling apparatus despite the absence of inflammation, and an increased capacity to produce TNF-α following LPS stimulation. Thus, depletion of CD11c(+) cells induces expansion of a unique CD64(+) Ly6C(+) monocyte population poised to synthesize TNF-α. This finding will require consideration in experiments using depletion strategies to test the role of CD11c(+) DCs in immunity.

Achieving immunoregulation via in vivo expansion of Foxp3+ regulatory CD4+ T cells (Treg) remains challenging. We have shown that mobilization confers to multipotent hematopoietic progenitors (MPPs) the capacity to enhance Treg proliferation. Transcriptomic analysis of Tregs co-cultured with MPPs revealed enhanced expression of genes stabilizing the suppressive function of Tregs as well as the activation of IL-1β-driven pathways. Adoptive transfer of only 25,000 MPPs effectively reduced the development of experimental autoimmune encephalomyelitis (EAE), a pre-clinical model for multiple sclerosis (MS). Production of the pathogenic cytokines IL-17 and GM-CSF by spinal cord-derived CD4+ T-cells in MPP-protected recipients was reduced while Treg expansion was enhanced. Treg depletion once protection by MPPs was established, triggered disease relapse to the same level as in EAE mice without MPP injection. The key role of IL-1β was further confirmed in vivo by the lack of protection against EAE in recipients of IL-1β-deficient MPPs. Mobilized MPPs may thus be worth considering for cell therapy of MS either per se or for enrichment of HSC grafts in autologous bone marrow transplantation already implemented in patients with severe refractory multiple sclerosis.

Research on human immunology has been hindered by the lack of optimal small animal models, given that the protective immune responses of human and non-human species show significant differences. However, due to ethical constraints[1] and the high cost of clinical trials, it is urgent to improve the current animal models that can mimic faithfully human physiology, particularly the human immune system (HIS). HIS mice had been generated recently by engrafting human hematopoietic stem cells (hHSCs) or human peripheral mononuclear cells (hPBMCs) into highly immuno-deficient mice such as NSG, NOG or NRG mice. However, a major experimental drawback for studies using these models is the rapid onset of Graft-versus-Host Disease (GvHD). In the present study, we overcome this limitation by generating new immuno-deficient mice named "HUMAMICE" (HLA-A2+/+/DR1+/+/H-2-β2m-/-/IAβ-/-/Rag2-/-/IL2rγ-/-/Perf-/- mice), which expressed human HLA molecules instead of mouse MHC molecules (H-2), and whose immuno-deficient status was reversed by transferring functional HLA-matched PBMCs thus producing mice with an immuno-competent status with a functional human immune system. We showed that in this HLA-matched context, the hPBMC-transfer led to high lymphocytes engraftment rates without GvHD over three months in this novel mouse model. Furthermore, to evaluate the utility of the hPBMC-HUMAMICE, we immunized them with commercial vaccine of Hepatitis B virus (HBsAg, Hepvac@) which resulted in robust and reproducible production of high levels of HBsAg-specific antibodies, implying that both transferred T and B lymphocytes were functional in HUMAMICE. These responses are comparable to those observed in human clinical trials with this identical vaccine. In conclusion, these findings indicated that the HLA-matched-hPBMC-HUMAMICE represents a promising model for dissecting human immune responses in various human diseases, including infectious diseases, cancers and tumors, and to facilitate the development of novel vaccines and cellular therapies.