MPLA and IFNγ Repolarize Macrophages to Promote Antitumor Immunity

Macrophages are innate immune effectors that can eliminate cancer cells, but in immunosuppressive tumor microenvironments, tumor-associated macrophages (TAM) often promote tumor growth and metastasis. Toll-like receptor agonists have been used to reprogram TAMs into classically activated macrophages with antitumor activity, but therapeutic efficacy in patients has been low. Sun and colleagues tested the antitumor effects of combining monophosphoryl lipid A (MPLA), a TLR4 agonist used as a vaccine adjuvant, with IFNγ, a critical cytokine for both innate and adaptive immunity approved for use in several diseases, in models of breast cancer. When macrophages and breast cancer cells derived from patients or tumor-bearing mice were cocultured, treatment with MPLA and IFNγ induced cancer cell killing by macrophages. The combination of MPLA and IFNγ increased transcription of tumoricidal macrophage markers such as NOS2 (encoding iNOS) and CD40, whereas TAM markers such as IL10 were decreased. When MPLA and IFNγ were tested in vivo, the combination inhibited primary tumor growth and prevented metastasis. Notably, MPLA and IFNγ not only increased secretion of immune cell–attracting chemokines and expression of type I IFN-inducible genes, but also repolarized TAMs into antitumor macrophages, increasing the proportion of macrophages expressing iNOS and CD40 while decreasing the proportion expressing CD206. In addition to the effect on macrophages, MPLA and IFNγ increased tumor infiltration of activated cytotoxic T cells and production of effector memory T cells. Specifically, the combination promoted macrophage-mediated cytotoxic T-cell activation, in part through macrophage secretion of IL12 and TNFα. Supporting the role of macrophage–T cell cross-talk in the effects of the combination, antibody depletion revealed that both macrophages and T cells were required for treatment-mediated inhibition of tumor growth and lung metastasis. Broadening the scope of these findings, MPLA and IFNγ also enhanced response to cisplatin in a murine model of metastatic ovarian cancer. In summary, this work highlights the therapeutic potential of combining two approved clinical agents to harness the antitumor efficacy of reprogrammed macrophages.

Sun L, Kees T, Santos Almeida A, Liu B, He X-Y, Ng D, et al. Activating a collaborative innate-adaptive immune response to control metastasis. Cancer Cell 2021 Sep 2 [Epub ahead of print].

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