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ABSTRACTImmune checkpoint inhibitors (ICIs) have provided new hope for melanoma patients, however, not all patients benefit. Furthermore, ICI©\related therapies cause significant immune©\related adverse events that adversely affect patient outcomes. Therefore, there is a pressing need for reliable biomarkers to identify patients most likely to benefit from these treatments. In this study, we employed an extracellular vesicles (EVs) protein expression array to explore the longitudinal membrane protein profiles of plasma©\derived EVs from 32 melanoma patients receiving anti©\PD©\1 and anti©\angiogenesis therapy at baseline and early treatment. We found that the dynamic changes in PD©\L2 on the EV membrane were associated with treatment response and patient survival. The dynamic change of EV PD©\L2 as an indication of treatment efficacy was validated in an independent cohort of melanoma patients treated with anti©\PD©\1 monotherapy. Plasma©\derived PD©\L2+ EVs from patients with mucosal melanoma significantly reduced the frequency of granzyme B+ CD8 T cells within the peripheral blood mononuclear cells (PBMCs) of healthy individuals. The inhibitory effect of PD©\L2+ EVs on CD8 T cells was further validated using human melanoma cell lines and the B16©\F10 mouse model. Although intratumoural injection of PD©\L2+ EVs could promote melanoma growth in vivo, tumours with PD©\L2+ EVs showed a higher response to anti©\PD©\1 than those without PD©\L2+ EVs. Collectively, our study demonstrates that PD©\L2+ EVs inhibit CD8 T cell activation and promote melanoma growth, and changes in PD©\L2 on circulating EVs during early treatment could serve as a biomarker for ICI©\based therapy.

IntroductionCD8+ T cells are vital in the immune control of cancer and a key player in cell-based cancer immunotherapy. Recent studies have shown that microbial short-chain fatty acids (SCFA) can promote both effector and memory phenotypes in CD8+ T cells and may thereby enhance protection against cancer.MethodsIn this study, we determined the effect of SCFA butyrate on mouse CD8+ T cell function in vitro and in vivo, using the OT-I model.ResultsButyrate co-culture with anti-CD3 + anti-CD28 activated T cells in vitro enhanced the frequency of effector CD8+ IFN-¦Ã-producing cells, and the amount of cytokine produced per cell. Culture with butyrate also enhanced the activation, TCR expression, and levels of phosphorylated mTOR proteins within CD8+ T cells but reduced proliferation rate and increased apoptosis. Butyrate-treated activated cells conferred tumor protection after adoptive transfer. Butyrate-treated cells were present at higher frequencies within the tumor compared to non-butyrate treated cells, and expressed IFN-¦Ã. When analyzed using high dimensional cytometry, the tumors of mice that received butyrate-treated cells were enriched in clusters displaying an effector memory phenotype with high expression of IL-15R¦Â and T-bet.DiscussionOur findings show that butyrate promotes the effector activity of CD8+ T cells in culture, which can persist in vivo while also stimulating memory phenotypes. Consequently, butyrate treatment may have strong application in T cell-based immunotherapies to improve protective cell functions and patient outcomes.

BackgroundLung cancer has become one of the most fatal cancers at present. Traditional treatments showed limited therapeutic effects on lung cancer. The phototherapy has emerged as a powerful approach for lung cancer treatment. Aggregation-induced emission luminogens (AIEgens) exhibit excellent optical performance such as strong fluorescence, enhanced reactive oxygen species (ROS) generation, and effective thermal effect after aggregation, which show great potential in phototherapy. However, the disadvantages including hydrophobicity, low specificity, and short circulation lifetime limited their efficacy on cancer therapy.MethodsWe developed a biomimetic AIEgens constructed using CD8+ T cells membrane to camouflage the AIEgen C41H37N2O3S2 (named BITT) nanoparticles (termed TB). The prepared TB improved the tumor accumulation of AIEgen by PD-1/PD-L1 recognition on the CD8+ T and LLC cell membranes, respectively.ResultsThe prepared TB showed improved binding efficiency, photothermal effects, and ROS generation ability to kill the lung cancer cells. TB also showed improved circulation lifetime and excellent tumor targeting ability, leading to effective phototherapy and immunotherapy in vivo based on BITT and the CD8+ T cell-derived membranes. Based on the AIE and immune checkpoint blockade (ICB) strategies, TB enhanced the antitumor activities of lung cancer by phototherapy and immunotherapy.ConclusionThe present work developed a type of biomimetic AIEgens, which overcame the inherent limitations of conventional AIEgens and leveraged immune recognition for targeted tumor accumulation. Furthermore, the integration of AIE-driven phototherapy with immune checkpoint blockade demonstrated potent synergistic antitumor efficacy, establishing a promising combinatorial strategy against aggressive lung malignancies.