Low lymphoma macrophage infiltration predicts poor outcomes for R-CHOP– but not Pola-R-CHP–treated patients with DLBCL

The influence of the tumor immune microenvironment (TME) on therapeutic efficacy remains unclear in diffuse large B-cell lymphoma (DLBCL), particularly for regimens incorporating antibody–drug conjugates (ADCs). We aimed to define the key lymphoma microenvironment factors associated with clinical outcomes in patients treated with anti-CD20 (rituximab [R] or obinutuzumab [G]) plus cyclophosphamide, doxorubicin, vincristine and prednisone (anti-CD20+CHOP), and understand how treatment with a modified, ADC-containing chemoimmunotherapy regimen alters the pre-treatment immune landscape’s influence on clinical outcome. We evaluated associations between TME composition and clinical outcomes in a harmonized dataset of 1,279 patients treated with either anti-CD20+CHOP or a modified regimen of anti-CD20-CHOP containing polatuzumab vedotin (Pola-R-CHP) across three clinical studies. We found that low enrichment of M1-like macrophages was consistently associated with inferior overall and progression-free survival in anti-CD20+CHOP-treated patients, suggesting these macrophages may facilitate antibody-mediated efficacy. In contrast, outcomes in polatuzumab vedotin-treated patients were independent of macrophage levels, supporting a mechanism of action driven primarily by ADC payload cytotoxicity. Other immune signatures that predicted outcome with anti-CD20+CHOP were also not prognostic with Pola-R-CHP. Our results indicate that ADCs may provide therapeutic benefit in patients with unfavorable immune microenvironments.