DISTINCT MONOCYTE STATES EMERGE DURING IMMUNE RECONSTITUTION AFTER BCMA CAR-T THERAPY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA
- 1A.C.Camargo Cancer Center, São Paulo, SP, Brasil
- 2Universidade Federal de Juiz de Fora, Minas Gerais, MG, Brasil
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.
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BibTeX
@article{silva2026distinct,
title = {{DISTINCT MONOCYTE STATES EMERGE DURING IMMUNE RECONSTITUTION AFTER BCMA CAR-T THERAPY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA}},
author = {Raquel GARCIA DA SILVA and Arianne FAGOTTI GUSMÃO and Vanessa DOS ANJOS BOVOLENTA and Daniela DELECHIAVE and Gabriel ANDRADE DE PAULA and Mariana SOARES GOMES and Ana Luiza SIONTI PACHECO and Larissa CAMPOS DE SOUZA and Filipe FREIRES DOS SANTOS and Ana COSTA CORDEIRO and Alexandre SILVA CHAVES and Marta Maria MOREIRA LEMOS and Marina DE MATTOS NASCIMENTO and Lais Lie SENDA DE ABRANTES and Sabrina PINHO COSTA MENDES and Mariela PIRES CABRAL PICCIN and Jayr SCHMIDIT FILHO and Marjorie VIEIRA BATISTA},
journal = {Hematology, Transfusion and Cell Therapy},
year = {2026},
month = oct,
doi = {10.1016/j.htct.2026.107862},
url = {https://doi.org/10.1016/j.htct.2026.107862},
note = {CC BY},
}
RIS
TY - JOUR
TI - DISTINCT MONOCYTE STATES EMERGE DURING IMMUNE RECONSTITUTION AFTER BCMA CAR-T THERAPY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA
AU - Raquel GARCIA DA SILVA
AU - Arianne FAGOTTI GUSMÃO
AU - Vanessa DOS ANJOS BOVOLENTA
AU - Daniela DELECHIAVE
AU - Gabriel ANDRADE DE PAULA
AU - Mariana SOARES GOMES
AU - Ana Luiza SIONTI PACHECO
AU - Larissa CAMPOS DE SOUZA
AU - Filipe FREIRES DOS SANTOS
AU - Ana COSTA CORDEIRO
AU - Alexandre SILVA CHAVES
AU - Marta Maria MOREIRA LEMOS
AU - Marina DE MATTOS NASCIMENTO
AU - Lais Lie SENDA DE ABRANTES
AU - Sabrina PINHO COSTA MENDES
AU - Mariela PIRES CABRAL PICCIN
AU - Jayr SCHMIDIT FILHO
AU - Marjorie VIEIRA BATISTA
PY - 2026
DA - 2026/10/23
JO - Hematology, Transfusion and Cell Therapy
DO - 10.1016/j.htct.2026.107862
UR - https://doi.org/10.1016/j.htct.2026.107862
AB - 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.
SN - 2531-1379
SN - 2531-1387
ER -