B cell–targeted therapies are increasingly used in oncology and autoimmunity, but their effects on mucosal immunity are not fully characterized. This study defines the pathophysiology of enterocolitis associated with B cell maturation antigen (BCMA)–targeted CAR-T cell therapy, a complication the authors designate CAR-TEC. The investigation combined high-resolution cellular and molecular approaches on intestinal biopsy material to map immune and stromal changes linked to this syndrome.
Intestinal biopsies were analyzed from three groups: patients with CAR-TEC (n = 10), CAR-T cell–treated controls without enterocolitis (n = 7) and healthy volunteers (n = 26). The authors applied single-cell transcriptomics, flow cytometry and tissue imaging to interrogate immune, stromal and epithelial compartments and to define cell-type–specific transcriptional programs and intercellular communication patterns.
A central finding was a pronounced depletion of mucosal B cells and plasma cells in CAR-TEC tissue. This loss of B lineage cells and antibody-secreting cells was a defining feature that differentiated affected biopsies from both CAR-T-treated controls and healthy mucosa. The observation links targeted BCMA-directed therapy with disruption of local humoral immunity in the gut.
CAR-TEC biopsies demonstrated expansion of highly cytotoxic CAR-T cells within the mucosa. The data indicate not only recruitment but persistence of antigen-directed CAR-T populations in the gut of affected patients, suggesting a tissue-resident or long-lived presence of engineered T cells that may drive local injury.
Beyond lymphoid changes, CAR-TEC was associated with broad inflammatory remodeling across non-lymphoid compartments. The authors report expansion and activation of inflammatory myeloid populations and alterations in stromal and glial cell types. These changes point to a multicellular mucosal reaction involving innate immune effectors and structural niche cells rather than an isolated lymphocyte-mediated effect.
Analyses of inferred cell–cell communication revealed distinct patterns in CAR-TEC compared with CAR-T-treated controls. While controls showed evidence of a compensated mucosal state after CAR-T therapy, CAR-TEC exhibited features consistent with telocyte-driven stromal niche dysfunction. Telocytes are specialized stromal cells implicated in tissue organization; their altered signaling in CAR-TEC suggests a stromal contribution to barrier dysfunction and persistent inflammation.
Transcriptional signatures in CAR-TEC tissues included upregulation of interferon-associated pathways and activation of JAK–STAT signaling programs across stromal, endothelial and epithelial cell populations. This convergent reprogramming implicates interferon-driven inflammation and downstream JAK–STAT–mediated transcriptional responses as common molecular features in multiple tissue compartments affected by CAR-TEC.
Because of the strong JAK–STAT signature across cell types, the authors propose JAK inhibition as a mechanism-based intervention. In the reported series, treatment with the oral selective JAK1 inhibitor upadacitinib resulted in clinical, endoscopic and histologic improvement in two people with CAR-TEC. These individual responses support the translational rationale but represent limited clinical experience reported in the source.
The study characterizes CAR-TEC as a multifactorial mucosal disorder associated with targeted B cell depletion, persistent and cytotoxic mucosal CAR-T cells, and broad inflammatory remodeling of myeloid, stromal and glial compartments. Interferon and JAK–STAT pathway activation across structural and epithelial cells provides a mechanistic basis for considering JAK1 inhibition; early use of upadacitinib produced improvement in two cases.
The source document supplied here is the article abstract and author information. Full methodological detail, expanded quantitative results, durability of responses to JAK inhibition, safety data and long-term outcomes were not reported in the provided source text. These elements would need to be consulted in the full article for comprehensive clinical interpretation and for informing treatment recommendations.