Tumor Microenvironment-Regulating Immunosenescence-Independent Nanostimulant Synergizing with Near-Infrared Light Irradiation for Antitumor Immunity.

The combination of photothermal therapy (PTT) and toll-like receptor (TLR)-mediated immunotherapy can elicit antitumor immunity and modulate the immunosuppressive tumor microenvironment (TME). Unlike other TLRs, TLR-5 is a promising target for immune activation, as its expression is well-maintained even during immunosenescence. Here, we developed a unique tumor microenvironment-regulating immunosenescence-independent nanostimulant consisting of TLR-5 adjuvant Vibrio vulnificus flagellin B (FlaB) conjugated onto the surface to an IR 780-loaded hyaluronic acid-stearylamine (HIF) micelles. These HIF micelles induced immune-mediated cell death via PTT when irradiated with a near-infrared laser. In comparison with PTT alone, the combination of in situ-generated tumor-associated antigens produced during PTT and the immune adjuvant FlaB demonstrated enhanced vaccine-like properties and modulated the TME by suppressing immune-suppressive regulatory cells (Tregs) and increasing the fraction of CD103+ migratory dendritic cells, which are responsible for trafficking tumor antigens to draining lymph nodes (DLNs). This combinatorial strategy (i.e., applying a TLR-5 adjuvant targeted to immunosenescence-independent TLR-5 and the in situ photothermal generation of tumor-associated antigens) is a robust system for next-generation immunotherapy and could even be applied in elderly patients, thus broadening the clinical scope of immunotherapy strategies.

Immunosenescence-like state is accelerated by constant light exposure and counteracted by melatonin or turmeric administration through DJ-1/Nrf2 and P53/Bax pathways.

The awareness of the interrelationship between immunosenescence and constant light exposure can provide new insights into the consequences of excessive exposure to light at night due to light pollution or shift work. Here, we investigated whether constant light exposure (LL) acts as an inducer of immunosenescence. We also determined the role of melatonin or turmeric in reversing the putative effects of constant light and explored for the first time the underlying molecular mechanisms. Young (3-4-month-old) rats were exposed daily to LL alone or in combination with each of melatonin and turmeric for 12 weeks. A group of aged rats (18-months old; n = 6) was used as a reference for natural immunosenescence. Constant light exposure resulted in remarkable pathophysiological alterations resembling those noticed in normal aged rats, manifested as apparent decreases in antioxidant activities as well as Nrf2 and DJ-1 expressions, striking augmentation in oxidative stress, proinflammatory cytokines and expression of TNFα, Bax, and p53 genes, and deleterious changes of lymphoid organs, Co-administration of melatonin or turmeric was able to reverse all alterations induced by LL through upregulation of Nrf2/DJ-1 and downregulation of p53/Bax pathways. These data suggest that LL accelerates immunosenescence via oxidative stress and apoptotic pathways. They also demonstrate for the first time that turmeric is comparable to melatonin in boosting the immune function and counteracting the LL-associated immunosenescence. These effects suggest that turmeric supplementation can be used as an inexpensive intervention to prevent circadian disruption-related immunosenescence. However, to validate the effects of turmeric on humans further studies are warranted.