The CCL17-CCR4 Axis Is Critical for Mutant STAT6-Mediated Microenvironmental Remodeling and Therapeutic Resistance in Relapsed/Refractory Diffuse Large B-Cell Lymphoma.

Relapsed and refractory diffuse large B-cell lymphoma (rrDLBCL) presents a significant challenge in hematology-oncology, with approximately 30% to 40% of patients with DLBCL experiencing relapse or resistance to treatment. This underscores the urgent need to better understand the molecular mechanisms governing therapeutic resistance. Signal transducer and activator of transcription 6 (STAT6) has been previously identified as a gene with recurrent D419 gain-of-function mutations in rrDLBCL. We demonstrated previously that when STAT6D419 mutations are present in DLBCL tumor cells, transcription of the chemokine CCL17 (aka TARC) is increased, and tumors have increased infiltration of CD4+ T cells. However, the implication of increased T-cell infiltration has not been reported previously. In the present study, we developed a mouse model of STAT6D419N mutant DLBCL that recapitulates the critical features of human STAT6D419-mutant DLBCL, including increased expression of phospho-STAT6, increased CD4+ T-cell invasion, and resistance to doxorubicin treatment. We report CD4+ T cells in STAT6D419N tumors exhibit higher expression of the receptor for CCL17, CCR4. Using ex vivo functional assays, we demonstrated that STAT6D419N tumor cells are directly chemoattractive to CCR4+ CD4+ T cells, and CCR4 inhibition using a small-molecule antagonist reduced CD4+ T-cell infiltration into STAT6D419N tumors and made STAT6D419N tumors regain therapeutic sensitivity to doxorubicin. Using PhenoCycler imaging of human rrDLBCL samples, we found that STAT6D419 tumors have increased expression of phospho-STAT6 and increased cellular interactions between phospho-STAT6+ tumor cells and CD4+/CCR4+ CD4+ T cells. Thus, our data identify CCR4 as a therapeutic target in STAT6D419-mutant rrDLBCL.