Evaluation of the Association Between Tumour Enrichment with M2-Macrophages and Survival Among South Africa Patients with Diffuse Large B-Cell Lymphoma

Abstract

Introduction Diffuse large B-cell lymphoma (DLBCL) is a subtype of non-Hodgkin lymphoma (NHL) which is common among people living with HIV. HIV-Associated DLBCL (HIV-DLBCL) has a more aggressive clinical course and generally poorer outcomes. Immunological derangements have prognostic associations in DLBCL among immunocompetent patients, and are thought to mirror the immune milieu of the tumour microenvironment (TME). Immune derangements are also common in people living with HIV. The primary hypothesis of this study was that the immune milieu of HIV-DLBCL differs from that seen in immunocompetent patients with DLBCL, and that this may account for the poorer outcomes generally seen in this setting. Methods Clinicopathological features of DLBCL diagnosed in Johannesburg were investigated, and seventy- six patients with incident DLBCL prospectively enrolled. Several immunological parameters were assessed, including immune cells (monocytes, lymphocytes, regulatory T-cells (Tregs), neutrophils and immunosuppressive monocytes), cytokines (interleukin [IL]6, IL10, Indoleamine 2,3- dioxygenase [IDO], ferritin, C-reactive protein [CRP] and serum free light chain [SFLC] levels), and the tumour macrophage burden assessed by immunohistochemistry on the diagnostic biopsies. These results were correlated with disease outcomes and the treatment received. Results Most patients (>80%) were people living with HIV, and outcomes were overall poor (one-year survival <40%). Differences in disease biology were evident, including higher rates of MYC-gene rearrangement and a lower frequency of BCL2-gene rearrangement as compared to that described in other parts of the world. The numbers of immune cells and tumour macrophages did not differ according to HIV-status, but the levels of several immunological proteins (including IL6, CRP, SFLC and IDO activity) were significantly higher among the patients with HIV. Notably, none of these variables had the same negative association with survival as seen among predominantly HIV-negative patients. Immunological abnormalities found to have a significant association with survival independently from the international prognostic index viii (IPI) included raised IL10, TGFB and ferritin levels, as well as low pro-inflammatory (M1) macrophage numbers. Anti-inflammatory (M2) macrophage numbers were not associated with outcomes, but appeared to be linked to a superior response to rituximab therapy. The serum ferritin was the only immunological parameter to show any correlation with tumour macrophage numbers, showing modest performance as a peripheral blood biomarker of the tumour macrophage burden. Conclusion HIV-DLBCL is a biologically and immunologically distinct entity. Immunological derangements are generally more pronounced and differ in their prognostic impact.