5-FU mediated depletion of myeloid suppressor cells enhances T-cell infiltration and anti-tumor response in immunotherapy-resistant lung tumor

by Selleckchem | Jul 19 2023

Tumor microenvironment (TME) is a heterogeneous system consisting of both cellular and acellular components. The growth and progression of tumors rely greatly on the nature of TME, marking it as an important target in cancer immunotherapy. Lewis Lung Carcinoma (LLC) is an established murine lung cancer model representing immunologically 'cold' tumors characterized by very few infiltrated cytotoxic T-cells, high levels of Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs). Here, we report various strategies we applied to reverse the non-immunogenic character of this cold tumor by imparting: a) immunogenic cell death using Hypericin nanoparticle-based photodynamic therapy (PDT), b) repolarising TAM using a TLR7/8 agonist, resiquimod, c) immune checkpoint inhibition using anti-PD-L1 and d) depleting MDSCs using low-dose 5-fluorouracil (5-FU) chemotherapy. Interestingly, the nano-PDT, resiquimod or anti-PD-L1 treatment had no major impact on tumor growth, whereas low-dose 5-FU-mediated depletion of MDSCs showed significant anti-tumor effect, primarily caused by the increased infiltration of CD8+ cytotoxic T-cells (∼96%). Though we have tested combining PDT with resiquimod or 5-FU for any synergistic effect, low-dose 5-FU alone showed better response than combinations. In effect, we show that depletion of MDSCs using low-dose 5-FU was one of the best methods to augment infiltration of CD8+ cytotoxic T-cells into a cold tumor, which is resistant to conventional therapies including immune checkpoint inhibitors.

Comments:

The study you described focuses on the tumor microenvironment (TME) and strategies to reverse the non-immunogenic character of Lewis Lung Carcinoma (LLC), a murine lung cancer model characterized by low immune cell infiltration and high levels of Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs).

The researchers applied various approaches to enhance the immune response within the tumor:

a) Immunogenic cell death using Hypericin nanoparticle-based photodynamic therapy (PDT): Immunogenic cell death refers to a form of cell death that stimulates an immune response against the tumor. In this case, Hypericin nanoparticle-based photodynamic therapy was used to induce immunogenic cell death within the tumor cells. However, it did not have a significant impact on tumor growth in this particular model.

b) Repolarizing TAMs using a TLR7/8 agonist, resiquimod: TAMs are immune cells present in the tumor microenvironment that can have both pro-tumor and anti-tumor functions. In this study, a Toll-like receptor 7/8 (TLR7/8) agonist called resiquimod was used to repolarize TAMs towards an anti-tumor phenotype. However, this approach did not show a major impact on tumor growth either.

c) Immune checkpoint inhibition using anti-PD-L1: Immune checkpoints are molecules that regulate the immune response, and their inhibition can help unleash the anti-tumor immune response. In this study, an anti-PD-L1 antibody was used to block the PD-L1 immune checkpoint. However, this treatment did not show a significant effect on tumor growth.

d) Depleting MDSCs using low-dose 5-fluorouracil (5-FU) chemotherapy: MDSCs are a type of immune cell that can suppress the anti-tumor immune response. Low-dose 5-fluorouracil chemotherapy was used to deplete MDSCs in the tumor microenvironment. This approach showed a significant anti-tumor effect, primarily attributed to the increased infiltration of CD8+ cytotoxic T-cells into the tumor. CD8+ T-cells are key immune cells involved in killing tumor cells.

Interestingly, the researchers also tested combinations of the different strategies mentioned above. However, low-dose 5-FU alone showed better results in terms of tumor response compared to the combinations.

In summary, the study highlights that depleting MDSCs using low-dose 5-FU chemotherapy was the most effective strategy to increase the infiltration of CD8+ cytotoxic T-cells in a cold tumor model like LLC, which is resistant to conventional therapies including immune checkpoint inhibitors. This research provides valuable insights into potential approaches for enhancing the immune response within the tumor microenvironment.