Pancreatic metastases are suppressed by photodynamic therapy and irinotecan through macrophage reprogramming in...

Pancreatic ductal adenocarcinoma (PDAC) exhibits early metastatic dissemination, dense desmoplastic stroma, and significant resistance to therapy. Our previous studies have shown that photodynamic therapy (PDT) combined with chemotherapy reduces the incidence of distant metastases in immunodeficient mouse models of PDAC. Given the absence of functional T cells in these models, we wondered why a local treatment reduced distant metastases. We hypothesized that the innate immune mechanisms, particularly macrophages, mediate the antimetastatic effects of PDT-chemotherapy combinations. To test this hypothesis, orthotopic xenograft tumors derived from metastatic human AsPC-1 PDAC cells were established in nude Swiss mice, and PDT with nanoliposomal irinotecan (nal-IRI) was evaluated in both pre-metastatic and advanced metastatic stages. In the pre-metastatic setting, combination therapy resulted in significant tumor regression, decreased stromal collagen, and reprogramming of TAMs from immunosuppressive to a pro-inflammatory phenotype. It increased natural killer (NK) cell recruitment and granzyme B-mediated cytotoxicity. In the advanced metastatic model, in which treatment was initiated after metastasis was established, a similar dominance of pro-inflammatory macrophage polarization was observed compared to pretreatment. However, these effects were less pronounced than observed with early intervention. Given the lack of pronounced polarization effects with either monotherapy alone, these findings suggest that PDT, when combined with nal-IRI, induces antitumor and antimetastatic responses by remodeling innate immunity, even in the absence of adaptive T-cell activity. It also supports macrophage polarization as a key mechanism underlying PDT-nal-IRI combination therapeutic increase both in local and distant tumor burden.