The transition between M1 and M2 macrophage phenotypes is associated with the disease status following CD19 CAR-T therapy for B cell lymphoma/leukemia

Although anti-CD19 chimeric antigen receptor (CAR-T) cells demonstrate high response rates in relapsed/refractory B-cell lymphomas, a considerable proportion of patients eventually encounter disease progression or relapse. The short-term and long-term outcomes of CAR-T treatment are intricately linked to the tumor microenvironment (TME), wherein macrophages with polarized characteristics can exhibit either anti-tumorigenic or pro-tumorigenic roles. Despite evidence implicating the crucial involvement of macrophages in CAR-T cell-treated lymphoma, their dynamic distribution and immune function related to lymphoma progression remain poorly understood. Immunocompetent mice were utilized to establish syngeneic A20 lymphoma/leukemia models. The distribution and polarization of macrophages were detected using immunohistochemistry (IHC) and flow cytometry techniques. We observed that CD19 CAR-T therapy exhibited significant efficacy in protecting mice against lymphoma, leading to increased infiltration of macrophages into the tumor tissue. Notably, during remission stages, M1-like macrophages (CD11b⁺F4/80⁺C206^-CD80⁺) were predominant, whereas in relapsed mice, there was a shift towards M2-like phenotypes (CD11b⁺F4/80⁺C206⁺CD80⁺). The transition from remissive to relapsed status was accompanied by a reduction in the M1/M2 ratio and a decrease in pro-inflammatory cytokines. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed differential expression levels of CD206 and CD163 between remissive and relapsed mice, while signaling pathways involving PI3K and STAT3 may contribute to the skewing towards M2 polarization. In summary, our findings highlight the dynamic transformation of macrophage polarization during different stages of lymphoma progression and underscore its potential implications for immunotherapeutic interventions.