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A preinfusion circulatory inflammation biomarker-based signature predicts the likelihood of treatment failure in patients with non-Hodgkin lymphoma who were treated with CAR-T cell therapy, with an inflammatory cluster assignment being prognostic of clinical response and survival outcomes.

Allogeneic chimeric antigen receptor (CAR) T cells are capable of inducing graft-versus-host disease (GVHD) in recipients, yet this is not commonly seen in the clinic. Marcel van den Brink, Michel Sadelain and colleagues show that alloreactive CAR T cells have reduced effector function due to signaling through the CAR and T cell receptor, resulting in reduced GVHD, while the graft-versus-leukemia effect is maintained by non-alloreactive CAR T cells.

The thymus is sensitive to acute insults including infection, as well as to injury from chemotherapy and myeloablative conditioning before hematopoietic cell transplantation. Here, Granadier et al. describe a role for IL-18 in limiting thymic regeneration by stimulating NK cells, which then target thymic epithelial cells.

In an analysis of adult patients with hematologic malignancies who received anti-CD19 chimeric antigen receptor T cell therapy, baseline gut microbiome composition was correlated with clinical response and treatment with broad-spectrum antibiotics in the four weeks prior to infusion was associated with worse survival and increased neurotoxicity.

Here the authors identify age-associated changes in the epithelial cell compartment of the thymus that form high-density nonproductive microenvironmental niches that contribute toward thymic involution and inhibit its repair following injury.

Hematopoietic stem cells (HSCs) differentiate into multiple lineages, with such capacity impacted by aging. Here the authors identify Kit^lo HSCs as a functionally distinct population that exhibits distinct lymphoid-primed chromatin landscapes, which drive enhanced lymphoid reconstitution capacity, and is altered in aged hosts.

Van den Brink and colleagues show that Nrf2, a regulator of the oxidative stress response, is required for several aspects of haematopoietic stem cell maintenance. Loss of Nrf2 results in the hyper-proliferation of haematopoietic stem and progenitor cells (HSPCs). Nrf2 is also required for HSPC migration and retention to their niche.

This Timeline article looks back over 50 years of haematopoietic stem cell transplantation as a cancer therapy, highlighting the substantial advances that have been made to increase the specificity of this treatment for cancer cells, as well as improvements in availability, safety and patient outcomes.

Targeted sequencing panels such as MSK-IMPACT have been successfully used to profile solid tumours in clinical settings. Here, the authors develop and implement the MSK-IMPACT Heme sequencing panel and platform to profile haematologic malignancies using paired tumor and normal tissues.

Analysis of the fungal and bacterial components of the intestinal microbiota of patients undergoing allogeneic haematopoietic cell transplantation identifies an association between fungal dysbiosis, an expansion of Candida parapsilosis complex species and worse patient outcomes.

A cell-sorting method leveraging leucine zippers allows for the generation of T cells displaying multiple chimaeric antigen receptors as well as receptors converting inhibitory signals into stimulatory signals.

The prodrug gliocidin effectively kills glioblastoma cells by targeting de novo purine synthesis, improving survival in mouse models.

The intestinal microbiota and its interactions with host immunity have been intensely studied in many disease states. This knowledge could ultimately modify clinical management of allogeneic haematopoietic stem cell transplantation, which is accompanied by dramatic immunological and microbiota perturbations.

A luteinizing hormone–releasing hormone antagonist, used clinically for sex-steroid inhibition, promotes quiescence of hematopoietic stem cells and thereby promotes hematopoietic recovery and survival of lethally irradiated mice.

Transplanting donor cells into lymph nodes regenerates liver, pancreas and thymus function in mice.

Graft-versus-host disease, a T cell-driven inflammatory condition, is associated with altered microbial bile acid metabolism in both mice and humans and this is linked to outcomes.

Poeck and colleagues identify a microbiome signature in patients receiving allogenic stem cell transplantation, which is associated with protective immune-modulatory metabolites, improved survival and less transplant-related mortality.

Increased relative abundance of oral bacteria in faecal samples can be explained by the marker hypothesis—their relative increase reflects the depletion of other microbiota members—which has implications for patient outcomes and microbiota-directed therapies.

Innate lymphoid cells increase the growth of mouse intestinal organoids via IL-22 production; recombinant IL-22 promotes growth of both mouse and human organoids, and promotes mouse intestinal stem cell (ISC) expansion and ISC-driven organoid growth via a STAT3-dependent pathway and independently of Paneth cells; IL-22 treatment in vivo enhances the recovery of ISCs from intestinal injury.

Influence of the gut microbiome on the human immune system is revealed by systems analysis of vast clinical data from decades of electronic health records paired with massive longitudinal microbiome sequencing.

Saavedra et al. show that broad-spectrum antibiotics impair homeostatic efferocytosis of macrophages in mice by affecting the gut microbiota. Microbial butyrate is shown to rescue homeostatic efferocytosis efficiency in vivo.

Pathogenesis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) remains unclear., Here the authors show in mouse models that dysbiosis caused by the expansion of Th/Tc22, as well as depletion of CX3CR1^hi mononuclear phagocytes resulted from the reduction of Th/Tc1, contributes to SR-Gut-aGVHD onset.

A limited T cell receptor (TCR) repertoire after allogeneic hematopoietic stem cell transplantation can be associated with poor clinical outcomes and greater susceptibility to infections. Jeroen van Heijst and colleagues have combined 5′ RACE PCR with deep sequencing technology to provide a reproducible and quantitative measure of the recovery of TCR diversity during the first year of transplantation with three commonly used stem cell sources in patients with various hematologic malignancies.

Thompson and colleagues show that repetitive antigenic stimulation within the tumor environment triggers mitochondrial dysfunction by inhibiting oxidative phosphorylation, which leads to T cell exhaustion.

The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.

The microbial metabolite sensor GPR43 has been previously shown to be a crucial modulator of immune responses. Here the authors show GPR43 is required for controlling disease pathology severity in the context of experimental models of GVHD.

Physiological effects of psychological stress and infection in mothers can increase the incidence of anxiety and psychiatric diseases in offsprings and in subsequent generation. Here, Miklos Toth and colleagues show that intergenerational inheritance of neurological traits is propagated across multiple generations independently by parallel non-genetic mechanisms involving independent segregation of epigenetic specific loci.

Expansion of pathogenic Candida species coupled with bacterial dysbiosis in the gut precedes Candida bloodstream infections in hematopoietic cell transplant recipients.

The gut commensal Blautia producta secretes a lantibiotic that reduces colonization of the gut by the major pathogen vancomycin-resistant Enterococcus faecium, and transplantation of microbiota with high abundance of the lantibiotic gene enhances resistance to colonization in mice.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a well-established treatment for many haematopoietic malignancies but often results in life-threatening complications, such as graft-versus-host disease, relapse and infections. This Review discusses the potential role of intestinal microbiota in complications after allo-HSCT.

A fraction of the intestinal microbiota as precise as a single bacterial species confers infection resistance by synthesizing Clostridium difficile-inhibiting metabolites from host-derived bile salts.

Reconstitution of the immune system after depletion by chemotherapy, radiotherapy, infection or transplantation is crucial to maintain protection from infection and to respond to immune-based therapy. Here the authors describe the ways in which a diverse T cell compartment can be restored, focusing on therapeutic strategies that drive the production of new T cells.

Strategies for inducing immunological tolerance to transplanted cells are an important component of regenerative therapies.