Mechanism of Heterodimeric IL-15 in tumor reduction: Induction of myeloid-lymphoid cell interactions leads to IFN-γ dependent lymphocyte recruitment by dendritic cells into tumors

Abstract Background hetIL-15 is evaluated in on-going immunotherapy clinical trials. We studied the mechanism of hetIL-15 antitumor function in several mouse models (MC38, TC-1, 4T1 and EO771). Methods We evaluated tumor immune infiltrate by flow cytometry, multi-color immunohistochemistry (IHC), transcriptomics and proteomics. Results hetIL-15 treatment delayed primary tumor growth, induced tumor regression and reduced metastases. Flow cytometry and IHC showed increased intratumoral NK and CD8+ T cell infiltration. Tumor-resident NK and CD8+ T cells were activated with enhanced IFN-γ production, increased proliferation (Ki67+), expression of survival factors (Bcl-2) and cytotoxic potential (Granzyme B+). hetIL-15 therapy resulted in increased IFN-γ and XCL1 levels and enhanced tumor accumulation of conventional type 1 dendritic cells (cDC1) expressing XCR1, IRF-8 and CD103. Production of CXCL9 and CXCL10 chemokines by tumor infiltrating cDC1 was boosted in an IFN-γ-dependent manner. Increased frequency of circulating NK and CD8+ T cells expressing CXCR3 was found, suggesting their migration toward tumors following the CXCL9/10 chemokine gradient. Conclusions hetIL-15 inhibits tumor growth by triggering lymphocyte-myeloid cell interactions modifying the tumor chemokine and cytokine milieu. hetIL-15 causes induction of XCL1 by lymphocytes, inducing DC intratumoral number, subsequent IFN-γ dependent CXCL9/10 production by DC and increased attraction of effector lymphocytes.