32P - Tumor growth inhibition effect of PLAG by regulation of neutrophil infiltration in ICI insensitivity B16F10 melanoma

Background

Malignant melanoma (MM) is a representative tumor with a low survival rate due to its early diagnosis difficulty and poor treatment efficacy. Melanoma usually promotes its growth via tumor-infiltrating neutrophils (TINs), which inhibit the activation of immune cells that prevent cancer cells such as cytotoxic T lymphocytes. Therefore, the best option for MM treatment is to prevent excessive neutrophil infiltration into cancer lessons.

Methods

A syngeneic model was used (n=6) to investigate the enhanced anti-tumor effect of anti-programmed cell death-ligand 1 (aPD-L1) with various dosages of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG). A B16F10 melanoma cell was subcutaneously inoculated into the C57BL/6 mice and maintained for 4 days. After that, PLAG was daily administered orally with different dosages (50/100/250 mpk) for 3 weeks with or without 10 mpk aPD-L1 (10F.9G2). PD-L1 antibody was delivered via IP injection once a week. Tumor growth was calculated in 3-day intervals.

Results

In this current study, we investigated the effects of PLAG and aPD-L1 in a B16F10 MM mouse model. We observed significant tumor growth inhibition in the mice treated with both PLAG and PLAG/aPD-L1, but not in aPD-L1 treated one (p<0.05). Abnormal levels of lymphocyte, neutrophil and neutrophil-to-lymphocyte ratio (NLR) shown in tumor-bearing mice were restored to normal in PLAG and PLAG/aPD-L1-treatment. In addition, the infiltration of active neutrophils (Ly6G and Myeloidperoxide positive) was significantly reduced. (p<0.05). The inability of active neutrophils to infiltrate the tumor massively is because PLAG significantly inhibited the release of factors that induce neutrophil maturation (G-CSF) and infiltration (Mip-2). In addition, PLAG effectively reduced the adenosine release in the tumor microenvironment (TME) and serum, thereby controlling unnecessary massive neutrophil migrations (p<0.05).

Conclusions

Collectively, our finding shows that PLAG effectively inhibits melanoma progression and may represent a novel therapeutic strategy for MM with high TINs, which is very difficult to use aPD-L1 therapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Enzychem Lifesciences.

Funding

Enzychem Lifesciences.

Disclosure

All authors have declared no conflicts of interest.