Lymphoma cell-driven IL-16 is expressed in activated B-cell-like diffuse large B-cell lymphomas and regulates the pro-tumor microenvironment

The activated B-cell-like subtype of diffuse large B-cell lymphoma (ABC-DLBCL) displays a worse outcome than the germinal center B-cell-like subtype (GCB-DLBCL). Currently, targeting the tumor microenvironment (TME) is the most promising approach to cure DLBCL with profound molecular heterogeneity; however, the factors affecting the tumor-promoting TME of ABC-DLBCL remain elusive. Here, cytokine interleukin-16 (IL-16) is expressed in tumor cells of ABC-DLBCL and secreted by the cleavage of active Caspase-3. The serum IL-16 levels are not only a sensitive marker of treatment response, but also positively correlated with unfavorable prognosis in DLBCL patients. While IL-16 shows few direct promotional effects on tumor cell growth in vitro, its bioactive form significantly promotes tumor progression in vivo. Mechanically, IL-16 increases the infiltration of macrophages by the chemotaxis of CD4+ monocytes in the TME, enhancing angiogenesis and the expression of cytokine IL-6 and IL-10, as well as decreasing T-cell infiltration to accelerate tumor progression. This study demonstrates that IL-16 exerts a novel role in co-ordinating the bidirectional interactions between tumor progression and the TME. IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα, reverses the tumor-promoting effects of IL-16, providing new insights into treatment strategy in ABC-DLBCL.