Mathematical modeling for the combination treatment of IFN-γ and anti-PD-1 in cancer immunotherapy

When the immune-checkpoint programmed death-1 (PD-1) binds to its ligand programmed death ligand 1 (PD-L1) to form the complex PD-1-PD-L1, this complex inactivates immune cells resulting in cell apoptosis, downregulation of immune reaction, and tumor evasion. The antibody, anti-PD-1 or anti-PD-L1, blocks the PD-1-PD-L1 complex formation to restore the functions of T cells. Combination of anti-PD-1 with other treatment shows promising in different types of cancer treatments. Interferon-gamma (IFN-γ) plays an important role in immune responses. It is mainly regarded as a pro-inflammatory cytokine that promotes the proliferation of CD8⁺ T cell and cytotoxic T cell, enhances the activation of Th1 cells and CD8⁺ T cells, and enhances tumor elimination. However, recent studies have been discovering many anti-inflammatory functions of IFN-γ, such as promotion of the PD-L1 expression, T cell apoptosis, and tumor metastasis, as well as inhibition of the immune recognition and the killing rates by T cells. In this work, we construct a mathematical model incorporating pro-inflammatory and anti-inflammatory functions of IFN-γ to capture tumor growth under anti-PD-1 treatment in the wild type and IFN-γ null mutant melanoma. Our simulation results qualitatively fit experimental data that IFN-γ null mutant with anti-PD-1 obtains the highest tumor reduction comparing to IFN-γ null mutant without anti-PD-1 and wild type tumor with anti-PD-1 therapy. Moreover, our synergy analysis indicates that, in the combination treatment, the tumor volume decreases as either the dosage of anti-PD-1 increases or the IFN-γ production efficiency decreases. Thus, the combination of anti-PD-1 and IFN-γ blockade improves the tumor reduction comparing to the monotherapy of anti-PD-1 or the monotherapy of IFN-γ blockade. We also find a threshold curve of the minimal dosage of anti-PD-1 corresponding to the IFN-γ production efficiency to ensure the tumor reduction under the presence of IFN-γ.