Photodynamic therapy changes tumour immunogenicity and promotes immune-checkpoint blockade response, particularly when combined with micromechanical priming

Abstract

Photodynamic therapy (PDT) with redaporfin stimulates colon carcinoma (CT26), breast (4T1) and melanoma (B16F10) cells to display high levels of CD80 molecules on their surfaces. CD80 overexpression amplifies immunogenicity because it increases same cell (cis) CD80:PD-L1 interactions, which (i) disrupt binding of T-cells PD-1 inhibitory receptors with their ligands (PD-L1) in tumour cells, and (ii) inhibit CTLA-4 inhibitory receptors binding to CD80 in tumour cells. In some cancer cells, redaporfin-PDT also increases CTLA-4 and PD-L1 expressions and virtuous combinations between PDT and immune-checkpoint blockers (ICB) depend on CD80/PD-L1 or CD80/CTLA-4 tumour overexpression ratios post-PDT. This was confirmed using anti-CTLA-4 + PDT combinations to increase survival of mice bearing CT26 tumours, and to regress lung metastases observed with bioluminescence in mice with orthotopic 4T1 tumours. However, the primary 4T1 responded poorly to treatments. Photoacoustic imaging revealed low infiltration of redaporfin in the tumour. Priming the primary tumour with high-intensity (~ 60 bar) photoacoustic waves generated with nanosecond-pulsed lasers and light-to-pressure transducers improved the response of 4T1 tumours to PDT. Penetration-resistant tumours require a combination of approaches to respond to treatments: tumour priming to facilitate drug infiltration, PDT for a strong local effect and a change in immunogenicity, and immunotherapy for a systemic effect.

Personalized Nanovaccines Enhance Lymph Node Accumulation and Reprogram the Tumor Microenvironment for Improved Photodynamic Immunotherapy

“…13,14 In addition, photodynamic therapy (PDT) mediated tumor ablation can be a neoadjuvant in situ for tumor vaccines. 15,16 However, PDT further exacerbated the limited oxygen depletion within the tumor microenvironment (TME), leading to tumor hypoxia. 17−19 If mitigation of tumor hypoxia can reprogram the TME, Fe 3 O 4 nanozyme possesses the potential to augment the immune efficacy of cancer vaccines.…”

“…However, the immune response activated by exogenous antigens or adjuvants alone cannot overcome the heterogeneity of solid tumors . One potential solution is to use patient-derived autologous tumor lysate pulsed Dex, effectively loading full range of tumor-associated antigens (TAAs). , In addition, photodynamic therapy (PDT) mediated tumor ablation can be a neoadjuvant in situ for tumor vaccines. , However, PDT further exacerbated the limited oxygen depletion within the tumor microenvironment (TME), leading to tumor hypoxia. − If mitigation of tumor hypoxia can reprogram the TME, Fe 3 O 4 nanozyme possesses the potential to augment the immune efficacy of cancer vaccines. , The DCs vaccines commonly used in clinical practice are typically activated in vitro and have a limited ability to migrate to lymph nodes (LNs) compared to naturally developed DCs in vivo. , TAAs are also expressed in normal tissues, which results in low affinity of immune recognition and ultimately a lack of high specificity for tumors . The high-density lipoprotein (HDL) served as an exquisite nanocarrier specifically designed for the targeted delivery of therapeutic drugs to lymphatic endothelial cells expressing scavenger receptor class B type I (SR-B1), effectively transporting antigenic peptides and TAAs to DCs. − HDL is also capable of enhancing the penetration of photosensitizers into specific barrier structures of solid tumors, sensitizing PDT and eradicated deep tumors. , …”