Distinct Monocyte States Emerge During Immune Reconstitution After Bcma Car-t Therapy in Relapsed/refractory Multiple Myeloma
Year: 2026
Type: article
Abstract: Background Relapsed/refractory multiple myeloma (RR-MM) remains a major therapeutic challenge despite the efficacy of BCMA-directed CAR-T therapy. However, mechanisms of innate immune reconstitution remain poorly understood. Monocytes regulate antigen presentation, inflammation, and immune homeostasis, with HLA-DR reflecting their functional state. Characterizing monocyte phenotypes may provide insights into post-CAR-T immune recovery. Aim To characterize monocyte phenotypic remodeling during immune reconstitution following BCMA CAR-T cell therapy and identify distinct immune states associated with impaired antigen-presenting profiles during immune reconstitution. Methodology: Patients with RR-MM treated with BCMA-directed CAR-T cells were prospectively enrolled. Peripheral blood samples were collected immediately before infusion (baseline) and 30 days post-infusion (D+30). Peripheral blood mononuclear cells were analyzed by multiparametric flow cytometry using CD45, CD14, CD16, HLA-DR, CD80, CD86, CD11b, CD11c, CD62L, CD19, and CD56. Monocyte subsets were defined according to CD14/CD16 expression and further characterized based on markers associated with antigen presentation, activation, co-stimulation, and migration. Changes in monocyte subset frequency and phenotype, including CD14⁺HLA-DR^low/- populations, were evaluated between baseline and D+30. Results Paired analysis of three patients demonstrated heterogeneous monocyte reconstitution after BCMA-directed CAR-T therapy. The patient with the highest circulating CAR-T cell frequency exhibited the most pronounced remodeling, with reduced total CD14⁺ and classical monocytes and relative expansion of non-classical monocytes. Across patients, classical monocytes shifted toward an HLA-DR-intermediate phenotype, while HLA-DR-negative intermediate monocytes consistently decreased. In patients with low baseline HLA-DR expression, this was accompanied by increased HLA-DR fluorescence intensity, suggesting partial restoration of antigen-presenting capacity. Co-stimulatory remodeling was subset-specific: HLA-DR⁺ intermediate monocytes showed increased CD80⁺CD86⁻ cells, whereas HLA-DR⁺ non-classical monocytes displayed increased CD80⁻CD86⁺ cells. Residual HLA-DR⁻ non-classical monocytes remained enriched for a CD80⁻CD86⁻ phenotype. Classical and intermediate monocytes were predominantly CD11b⁺CD11c⁺, while non-classical monocytes exhibited greater CD11b/CD11c heterogeneity. Discussion: These findings suggest that early immune reconstitution following BCMA-directed CAR-T therapy is characterized by heterogeneous rather than uniform monocyte recovery. The reduction of HLA-DR-negative intermediate monocytes may indicate partial restoration of antigen presentation, whereas persistence of HLA-DR⁻CD80⁻CD86⁻ non-classical monocytes suggest incomplete recovery of co-stimulatory function. CD11b/CD11c heterogeneity further supports the existence of distinct activation and migratory states within the monocyte compartment. Conclusion Early immune reconstitution after BCMA-directed CAR-T therapy is associated with dynamic remodeling of monocyte subsets and partial recovery of antigen-presenting phenotypes. Persistent HLA-DR⁻ non-classical monocytes may represent a distinct immune state associated with incomplete innate immune recovery. These findings support further investigation of monocyte functional states as biomarkers of immune reconstitution following CAR-T therapy.
Authors: Raquel GARCIA DA SILVA, Arianne FAGOTTI GUSMÃO, Vanessa DOS ANJOS BOVOLENTA, Daniela DELECHIAVE, Gabriel ANDRADE DE PAULA, Mariana SOARES GOMES, Ana Luiza SIONTI PACHECO, Larissa CAMPOS DE SOUZA, Filipe FREIRES DOS SANTOS, Ana COSTA CORDEIRO, Alexandre SILVA CHAVES, Marta Maria MOREIRA LEMOS, Marina DE MATTOS NASCIMENTO, Lais Lie SENDA DE ABRANTES, Sabrina PINHO COSTA MENDES, Mariela PIRES CABRAL PICCIN, Jayr SCHMIDIT FILHO, Marjorie VIEIRA BATISTA
Institution: AC Camargo Hospital
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223152425