Elimination of Metastatic Melanoma Using Gold Nanoshell-Enabled Photothermal Therapy and Adoptive T Cell Transfer

Abstract

Ablative treatments such as photothermal therapy (PTT) are attractive anticancer strategies because they debulk accessible tumor sites while simultaneously priming antitumor immune responses. However, the immune response following thermal ablation is often insufficient to treat metastatic disease. Here we demonstrate that PTT induces the expression of proinflammatory cytokines and chemokines and promotes the maturation of dendritic cells within tumor-draining lymph nodes, thereby priming antitumor T cell responses. Unexpectedly, however, these immunomodulatory effects were not beneficial to overall antitumor immunity. We found that PTT promoted the infiltration of secondary tumor sites by CD11b+Ly-6G/C+ myeloid-derived suppressor cells, consequently failing to slow the growth of poorly immunogenic B16-F10 tumors and enhancing the growth of distant lung metastases. To exploit the beneficial effects of PTT activity against local tumors and on antitumor immunity whilst avoiding the adverse consequences, we adoptively transferred gp100-specific pmel T cells following PTT. The combination of local control by PTT and systemic antitumor immune reactivity provided by adoptively transferred T cells prevented primary tumor recurrence post-ablation, inhibited tumor growth at distant sites, and abrogated the outgrowth of lung metastases. Hence, the combination of PTT and systemic immunotherapy prevented the adverse effects of PTT on metastatic tumor growth and optimized overall tumor control.

Elimination of epithelial-like and mesenchymal-like breast cancer stem cells to inhibit metastasis following nanoparticle-mediated photothermal therapy

“…Development of imagable, targeted nanoparticles may even allow for localized PTT at sites of macrometastases. Perhaps most promising are the initial findings that nanoparticle-mediated hyperthermia induces a systemic cancer-specific immune response in which cytotoxic T-cells are trained to recognize and inhibit distal cancer cells [36], a response that may be strengthened by coupling with immunotherapy [32,39], suggesting the potential to inhibit already formed micro- and macrometastases in human patients.…”

Immunomodulating Nanomedicine for Cancer Therapy

“…For example, photothermal therapy (PTT) using gold nanoshells was shown to effectively ablate local tumors, releasing endogenous immunostimulatory molecules and promoting subsequent activation of dendritic cells. 30 Even stronger antitumor immune responses can be achieved by combination therapies. For example, PTT in combination with ICD-inducing chemotherapeutic agents or immunomodulating agents have been shown to synergistically elicit systemic antitumor immunity that can eliminate local tumors directly treated with PTT as well as untreated, disseminated tumors in multiple tumor models.…”

Development of individualized anti-metastasis strategies by engineering nanomedicines

“…In addition, Au nanoshells and nanoparticles were also developed for theranostics (NIR-photothermal therapy and imaging) of metastatic tumours by T cell-mediated delivery. 283, 284 The efficiency of T cell-mediated delivery of nanomedicines to tumours increased considerably compared to nanomedicines alone. However, their biodistribution results demonstrated that a large amount of nanomedicines also accumulated on multiple other sites including bone, liver, spleen and lung.…”