Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma

Abstract

Background The PD-L1 antibody is an immune checkpoint inhibitor (ICI) attracting attention. The third-generation anticancer drug has been proven to be very effective due to fewer side effects and higher tumor-specific reactions than conventional anticancer drugs. However, as tumors produce additional resistance in the host immune system, the effectiveness of ICI is gradually weakening. Therefore, it is very important to develop a combination therapy that increases the anticancer effect of ICI by removing anticancer resistance factors present around the tumor. Methods The syngeneic model was used (n = 6) to investigate the enhanced anti-tumor effect of PD-L1 antibody with the addition of PLAG. MB49 murine urothelial cancer cells were implanted into the C57BL/6 mice subcutaneously. PLAG at different dosages (50/100 mpk) was daily administered orally for another 4 weeks with or without 5 mpk PD-L1 antibody (10F.9G2). PD-L1 antibody was delivered via IP injection once a week. Results The aPD-L1 monotherapy group inhibited tumor growth of 56% compared to the positive group, while the PLAG and aPD-L1 co-treatment inhibited by 89%. PLAG treatment effectively reduced neutrophils infiltrating localized in tumor and converted to a tumor microenvironment with anti-tumor effective T-cells. PLAG increased tumor infiltration of CD8 positive cytotoxic T-cell populations while effectively inhibiting the infiltration of neoplastic T-cells such as CD4/FoxP3. Eventually, neutrophil-induced tumor ICI resistance was resolved by restoring the neutrophil-to-lymphocyte ratio to the normal range. In addition, regulation of cytokine and chemokine factors that inhibit neutrophil infiltration and increase the killing activity of cytotoxic T cells was observed in the tumors of mice treated with PLAG + aPD-L1. Conclusions PLAG effectively turned the tumor-promoting microenvironment into a tumor-suppressing microenvironment. As a molecule that increases the anti-tumor effectiveness of aPD-L1, PLAG has the potential to be an essential and effective ICI co-therapeutic agent.

Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival

“…Animals were treated with PD-L1 antibody alone and in combination with 1-palitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG). The results of this study showed that the number of neutrophils infiltrating the tumour tissue decreased considerably in the PLAG- and PD-L1 antibody-treated groups and the population of cytotoxic T-cell cells increased substantially ( 72 ). This study clearly validated the role of PD-L1 in immune suppression and its association with lactate acidosis in solid hypoxic tumours.…”

Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies

“…Quantitative proteomic analysis of patients’ plasma revealed a possible role for the HGF-MET pathway in LDN-dependent resistance to anti-PD-1 therapy, suggesting the combination of MET inhibitors, known agents in cancer therapy, with anti-PD-1/PD-L1 therapy as an alternative approach [ 83 , 296 ]. A recent study found that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) inhibited neutrophil infiltration to the tumor and normalized NLR in a mouse urothelial carcinoma model [ 237 ]. The co-administration of PLAG and anti-PD-L1 therapy has improved the latest anticancer effect, suggesting a new approach to overcome anti-PD-1/PD-L1 resistance [ 237 ].…”

“…A recent study found that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) inhibited neutrophil infiltration to the tumor and normalized NLR in a mouse urothelial carcinoma model [ 237 ]. The co-administration of PLAG and anti-PD-L1 therapy has improved the latest anticancer effect, suggesting a new approach to overcome anti-PD-1/PD-L1 resistance [ 237 ]. In HCC, lactate, produced by tumor cells, was found to be involved in PD-L1 expression on neutrophils via the MCT1/NF-kB/COX-2 pathway, which inhibited the effect of lenvatinib.…”

“…More promising strategies are to block neutrophil immunosuppressive function or to restore neutrophil anti-tumor properties. ( 2 ) MET inhibitors [ 83 ], PLAG [ 237 ], COX inhibitors [ 238 ], and CCL20 inhibitors [ 123 ] could inhibit neutrophil immunosuppressive functions and restore the efficiency of ICIs. ( 3 ) To restore neutrophil anti-tumor activities, TGF-β inhibitors [ 14 ], lorlatinib [ 233 ], and some selected bioactive compounds (berberine [ 239 ], salidroside [ 240 ], and emodin [ 241 ]) are considered reliable choices.…”