Intra-tumoral lactate accumulation and acidosis impair T cell function and anti-tumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, is prognostic for the survival of rectal cancer patients, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance.
To determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor were investigated in a colon carcinoma (CRC) tumor spheroid models co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with anti-PD L1 antibodies.
Inhibition of MCT4 was sufficient to reduce lactate efflux in 3D CRC spheroids but not in 2D cell-cultures. Co-administration of the MCT4 inhibitor and ICB augmented immune cell infiltration, T cell function and decreased CRC spheroid viability in a 3D co-culture model of human CRC spheroids with blood leukocytes. Accordingly, combination of MCT4 and ICB increased intra-tumoral pH, improved leukocyte infiltration and T cell activation, delayed tumor growth, and prolonged survival in vivo. MCT1 inhibition exerted no further beneficial impact.
These findings demonstrate that single MCT4 inhibition represents a novel therapeutic approach to reverse lactic-acid driven immunosuppression and might be suitable to improve ICB efficacy
