Despite the potential efficacy of immune checkpoint blockade for effective treatment of cancer, this therapeutic modality is not generally curative, and only a fraction of patients respond. Combination approaches provide strategies to target multiple antitumor immune pathways to induce synergistic antitumor immunity. Here, a multi-combination immunotherapy, including photothermal therapy (PTT), indoleamine-2,3-dioxygenase (IDO) inhibition, and programmed cell death-ligand 1 (PD-L1) blockade, is introduced for inducing synergistic antitumor immunity. We designed a multifunctional IDO inhibitor (IDOi)-loaded reduced graphene oxide (rGO)-based nanosheets (IDOi/rGO nanosheets) with the properties to directly kill tumor cells under laser irradiation and in situ trigger antitumor immune response. In vivo experiments further revealed that the triggered immune response can be synergistically promoted by IDO inhibition and PD-L1 blockade; the responses included the enhancement of tumor-infiltrating lymphocytes, including CD45 + leukocytes, CD4 + T cells, CD8 + T cells, and NK cells; the inhibition of the immune suppression activity of regulator T cells (T regs ); and the production of INF-γ. We also demonstrate that the three combinations of PTT, IDO inhibition, and PD-L1 blockade can effectively inhibit the growth of both irradiated tumors and tumors in distant sites without PTT treatment. This work can be thought of as an important proof of concept to target multiple antitumor immune pathways to induce synergistic antitumor immunity.
Bibliographical noteFunding Information:
We acknowledge financial support from the National Natural Science Foundation of China (nos. 81673027, 31670948 and 31600743), Tianjin Natural Science Fund for Distinguished Young Scholars (17JCJQJC46400), CAMS Innovation Fund for Medical Sciences (CAMS-I2M-3-026), and Specific Program for High-Tech Leader & Team of Tianjin Government.
© 2018 American Chemical Society.
- IDO inhibition
- combinatorial immunotherapy
- photothermal therapy
- reduced graphene oxide