Abstract 1796: PD-L1 photoimmunotherapy kills immunosuppressive myeloid cells to activate local and systemic antitumor immunity in syngeneic mouse models
Authors: Thorne Amy H. , Hsu Michelle H. , Mendoza Daniel , Lapetoda Jason , Parry Christopher M. , Fong Jerry J. , Garcia-Guzman Miguel 
Published: July 2021

Introduction: Photoimmunotherapy is an investigational anticancer treatment platform that combines the cell surface binding of an antibody conjugated to a light activatable dye (IRDye® 700DX, IR700) with non-thermal red light illumination for selective cell killing. PD-L1, the target of anti-PD-L1 inhibitors, is a suppressive checkpoint marker expressed on tumor cells and immunosuppressive myeloid cells in the tumor microenvironment. Here we examined the anticancer activity and immune activation elicited by anti-PD-L1-IR700 photoimmunotherapy (PD-L1 photoimmunotherapy).

Methods: CT26 or LL/2 tumors were used to assess antitumor immune response following PD-L1 photoimmunotherapy. CT26PD-L1-/- tumors were generated by CRISPR/Cas9. Tumor volume was determined by caliper measurements in illuminated and non-illuminated tumors. Intratumoral immune responses were assessed by flow cytometry. Complete responder (CR) mice were challenged with either CT26 or 4T1 tumors to evaluate immune memory.

Results: Mice bearing CT26 or LL/2 tumors treated with PD-L1 photoimmunotherapy exhibited a notable reduction of tumor growth compared to mice that received control treatments (saline, anti-PD-L1-IR700 conjugate alone without illumination, or multi-dosing with anti-PD-L1 antibody). Pre-treatment depletion of CD8+ T cells in the mice abrogated the antitumor activity of PD-L1 photoimmunotherapy, demonstrating a key role of CD8+ T-cell effector activity in the responses. PD-L1 photoimmunotherapy induced CRs in 7/15 mice, and all CR mice rejected CT26 tumor growth after re-challenge, indicating the generation of immunological memory. Furthermore, 6/8 mice rejected inoculation of 4T1 tumors, suggesting an enhanced ability to prime new T cells with tumor neoantigens. Intratumoral immune cell analysis showed a reduction of myeloid cells 2 hours following illumination, an increase of CD103+ dendritic cells 2 days following illumination, and an increase of non-exhausted PD-1-CD8+ T effector cells 8 days after illumination. In a bilateral tumor model, PD-L1 photoimmunotherapy resulted in tumor reduction in the non-illuminated tumor. Mice bearing CT26PD-L1-/- tumor cells similarly exhibited tumor reduction after PD-L1 photoimmunotherapy, suggesting that antitumor activity resulted from the elimination of PD-L1+ non-tumor cells.

Conclusions: PD-L1photoimmunotherapy induces anticancer responses by killing PD-L1+ myeloid cells and possibly PD-L1+ cancer cells within the tumor, resulting in augmentation of local and systemic antitumor immunity. These results indicate that PD-L1 photoimmunotherapy can elicit anticancer immune responses in target and distal tumors, including syngeneic mouse models refractory to checkpoint inhibition.

Citation Format: Amy H. Thorne, Michelle H. Hsu, Daniel Mendoza, Jason Lapetoda, Christopher M. Parry, Jerry J. Fong, Miguel Garcia-Guzman. PD-L1 photoimmunotherapy kills immunosuppressive myeloid cells to activate local and systemic antitumor immunity in syngeneic mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1796.