Immunotherapy Enhancement by Targeting Extracellular Tumor pH in Triple-Negative Breast Cancer Mouse Model

Area of Science:

• Immunology
• Oncology
• Cancer Biology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with poor survival rates.
• Immunotherapy targeting immune checkpoints like PD-L1 shows promise but has limited efficacy in TNBC.
• Tumor microenvironment acidity (Warburg effect) impairs anti-tumor immune responses and contributes to immunotherapy resistance.

Purpose of the Study:

• To investigate if oral sodium bicarbonate (NaHCO3) can enhance the efficacy of anti-PD-L1 immunotherapy in TNBC.
• To explore the impact of NaHCO3 on the tumor microenvironment and immune cell activity.
• To assess the potential of combining alkalizing therapy with immune checkpoint blockade for TNBC.

Main Methods:

• Utilized a 4T1-Luc TNBC mouse model.
• Administered sodium bicarbonate (NaHCO3) orally, alone and in combination with anti-PD-L1 antibody.
• Assessed tumor growth, survival, tumor extracellular pH (pHe), T cell infiltration and activation, and cytokine mRNA expression (IFN-γ, IL2, IL12p40).

Main Results:

• Oral NaHCO3 significantly enhanced the antitumor effects of anti-PD-L1 therapy, leading to tumor growth inhibition and improved survival.
• NaHCO3 treatment increased tumor extracellular pH (pHe), promoted T cell infiltration and activation within tumors, and boosted T cell activity in draining lymph nodes.
• Combined NaHCO3 and anti-PD-L1 therapy showed synergistic effects, further enhancing anti-tumor immunity. Acidic conditions in vitro increased PD-L1 expression.

Conclusions:

• Alkalizing therapy with sodium bicarbonate holds potential as a novel immunomodulator for the tumor microenvironment.
• Combining NaHCO3 with anti-PD-L1 immunotherapy can overcome resistance mechanisms and improve treatment outcomes in TNBC.
• This combination strategy offers a promising personalized medicine approach to enhance immunotherapy efficacy in TNBC patients.