Tumor-associated
inflammation mediates the development of a systemic immunosuppressive milieu that is a major obstacle to effective treatment of
cancer.
Inflammation has been shown to promote the systemic expansion of immature myeloid cells which have been shown to exert immunosuppressive activity in laboratory models of
cancer as well as
cancer patients. Consequentially, significant effort is underway toward the development of
therapies that decrease
tumor-associated
inflammation and immunosuppressive cells. The current study demonstrated that a previously described deep tissue imaging modality, which utilized
indocyanine green-loaded
calcium phosphosilicate nanoparticles (ICG-CPSNPs), could be utilized as an immunoregulatory agent. The
theranostic application of ICG-CPSNPs as
photosensitizers for
photodynamic therapy was shown to block
tumor growth in murine models of
breast cancer,
pancreatic cancer, and metastatic
osteosarcoma by decreasing
inflammation-expanded immature myeloid cells. Therefore, this therapeutic modality was termed PhotoImmunoNanoTherapy. As phosphorylated
sphingolipid metabolites have been shown to have immunomodulatory roles, it was hypothesized that the reduction of immature myeloid cells by PhotoImmunoNanoTherapy was dependent upon bioactive
sphingolipids. Mechanistically, PhotoImmunoNanoTherapy induced a
sphingosine kinase 2-dependent increase in
sphingosine-1-phosphate and
dihydrosphingosine-1-phosphate. Furthermore,
dihydrosphingosine-1-phosphate was shown to selectively abrogate myeloid lineage cells while concomitantly allowing the expansion of lymphocytes that exerted an antitumor effect. Collectively, these findings revealed that PhotoImmunoNanoTherapy, utilizing the novel nontoxic
theranostic agent ICG-CPSNP, can decrease
tumor-associated
inflammation and immature myeloid cells in a
sphingosine kinase 2-dependent manner. These findings further defined a novel myeloid regulatory role for
dihydrosphingosine-1-phosphate. PhotoImmunoNanoTherapy holds the potential to be a revolutionary treatment for
cancers with inflammatory and immunosuppressive phenotypes.