Abstract
BackgroundTumor-associated macrophages (TAMs) are the most abundant stromal cells in the tumor microenvironment. Turning the TAMs against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically “cold” tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells’ immunogenicity and thereby reactivate the TAMs into the anti-tumor M1 phenotype.ResultsNano-DOX were first shown to stimulate the tumor cells and the TAMs to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAMs. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1’s action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAMs both by blocking Nano-DOX-induced PD-L1 in the TAMs and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAMs with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX’s action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner.ConclusionsPD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAMs to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAMs, achieves enhanced activation of TAM-mediated anti-tumor response.Graphic abstract
Highlights
Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death-1 (PD-1), are vital negative regulators of immune cell activation
Our previous work had demonstrated that Nano-DOX could stimulate glioblastoma cells to release damage-associated molecular patterns (DAMPs) including high mobility group box 1 (HMGB1), adenosine triphosphate (ATP), heat shock protein 90 (HSP90), and calreticulin (CRT) [14]
In agreement with their capacity to stimulate DAMPs release, both DOX and Nano-DOX impaired the viability of non-small cell lung cancer (NSCLC) cells, with higher potency seen with DOX (Additional file 1: Figure S1 A, B)
Summary
Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death-1 (PD-1), are vital negative regulators of immune cell activation. Therapies that block PD-L1/PD-1 interaction between cancer cells and T cells promoting antitumor immunity have shown remarkable clinical efficacy in the treatment of a variety of malignant diseases [2,3,4] These immunotherapies are largely ineffective in tumors with lymphocyte exhaustion or poor lymphocyte infiltration, a condition termed immunologically “cold” tumor [5,6,7]. It is intriguing to envision that blocking the PD-L1/PD-1 interaction between cancer cells and TAMs through anti-PD-L1/PD-1 therapy may turn the TAMs against their host cancer cells and achieve therapeutic efficacy, in those immunologically cold tumors The success of this strategy will hinge on the expression status of PD-L1/PD-1 in the tumor cells, the TAMs, and the activation phenotype of TAMs. Tumor-associated macrophages (TAMs) are the most abundant stromal cells in the tumor microenvi‐ ronment. Nano-DOX are an agent previously proved to be able to stimulate tumor cells’ immunogenicity and thereby reactivate the TAMs into the anti-tumor M1 phenotype
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