Thayer School of Engineering
Photodynamic priming (PDP), a collateral effect of photodynamic therapy, can transiently alter the tumor microenvironment (TME) beyond the cytotoxic zone. Studies have demonstrated that PDP increases tumor permeability and modulates immune-stimulatory effects by inducing immunogenic cell death, via the release of damage-associated molecular patterns and tumor-associated antigens. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of cancers with a stubborn immunosuppressive TME and a dense stroma, representing a challenge for current molecular targeted therapies often involving macromolecules. We, therefore, tested the hypothesis that PDP's TME modulation will enable targeted therapy and result in immune stimulation. Using triple-receptor-targeted photoimmuno-nanoconjugate (TR-PINs)-mediated PDP, targeting epidermal growth factor receptor, transferrin receptor, and human epidermal growth factor receptor 2 we show light dose-dependent TR-PINs mediated cytotoxicity in human PDAC cells (MIA PaCa-2), co-cultured with human pancreatic cancer-associated fibroblasts (PCAFs) in spheroids. Furthermore, TR-PINs induced the expression of heat shock proteins (Hsp60, Hsp70), Calreticulin, and high mobility group box 1 in a light dose and time-dependent manner. TR-PINs-mediated T cell activation was observed in co-cultures of immune cells with the MIA PaCa-2-PCAF spheroids. Both CD4+ T and CD8+ T cells showed light dose and time-dependant antitumor reactivity by upregulating degranulation marker CD107a and interferon-gamma post-PDP. Substantial tumor cell death in immune cell-spheroid co-cultures by day 3 shows the augmentation by antitumor T cell activation and their ability to recognize tumors for a light dose-dependent kill. These data confirm enhanced destruction of heterogeneous pancreatic spheroids mediated by PDP-induced phototoxicity, TME modulation and increased immunogenicity with targeted nanoconstructs.
De Silva, Pushpamali, Bano, Shazia, Pogue, Brian W., Wang, Kenneth K., Maytin, Edward V. and Hasan, Tayyaba. "Photodynamic priming with triple-receptor targeted nanoconjugates that trigger T cell-mediated immune responses in a 3D in vitro heterocellular model of pancreatic cancer" Nanophotonics, vol. 10, no. 12, 2021, pp. 3199-3214. https://doi.org/10.1515/nanoph-2021-0304
Dartmouth Digital Commons Citation
De Silva, Pushpamali; Bano, Shazia; Pogue, Brian W.; Wang, Kenneth K.; Maytin, Edward V.; and Hasan, Tayyaba, "Photodynamic priming with triple-receptor targeted nanoconjugates that trigger T cell-mediated immune responses in a 3D in vitro heterocellular model of pancreatic cancer" (2021). Dartmouth Scholarship. 4239.