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, 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 or obinutuzumab) plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; anti-CD20 + CHOP) and to understand how treatment with a modified, ADC-containing chemoimmunotherapy regimen alters the influence of the pretreatment immune landscape on clinical outcome. We evaluated associations between TME composition and clinical outcomes in a harmonized data set of 1279 patients treated with either anti-CD20 + CHOP or a modified regimen of anti-CD20 + CHOP containing polatuzumab vedotin (Pola-R-CHP) across 3 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 that 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 treatment were also not prognostic with Pola-R-CHP treatment. Our results indicate that ADCs may provide therapeutic benefit to patients with unfavorable immune microenvironments. These trials were registered at www.clinicaltrials.gov as #NCT01287741, #NCT00486759, and #NCT03274492.