To prove this idea, DOX and BMS-202 (a PD-L1 blocker) were loaded to black phosphorus (BP) nanoparticles after dosage titration to yield the BMS-202/DOX@BP composites that rapidly disintegrated and released drug cargo upon mild photothermal heating at 40 °C. The synergetic actions involved highlight the value of TAM and the significance of modulating tumor cell-TAM cross-talk in tumor therapy. Photothermia-responsive BP provides an efficient platform to translate this strategy into targeted, efficacious tumor therapy.
Mechanistically, it reduces the expression of PD-L1 on the surface of GBM cells and interrupts the PD-L1-AKT-BCAT1 axis independent of mTOR signaling. Taken together, we conclude that BMS-202 is a promising therapeutic candidate for patients with GBM by remodeling their cell metabolism regimen, thus leading to better survival.
Meanwhile, the liberated BMS202 blocks immune checkpoints on tumor cells and T cells, activating the recruited T cells and ultimately eradicating the tumors. This innovative strategy represents a comprehensive approach to fine-tune the TME, significantly amplifying the effectiveness of cancer immunotherapy by exploiting the TRPV1 pathway and enabling in situ control of immunomodulation within the TME.
Further mechanistic analysis confirmed that BMS-202 antagonizes UV-induced PD-L1 expression both at the mRNA and protein levels in SKH-1 epidermis. These data suggest that topical pharmacological PD-L1 antagonism using BMS-202 shows promise for skin protection against photodamage.
PET imaging with [Ga]Ga-D-pep-PMED, a small-molecule radiotracer, is a promising tool for evaluating PD-L1 expression and quantifying the target blockade of PD-L1 to assist in the development of effective therapeutic regimens.
The hydrogel was created by sodium alginate (SA) as the gelator, where linagliptin particles and BMS-202 particles were present in hydrogel micropores. Therefore, the hydrogel in combination with CXCL10 demonstrated powerful cancer immunotherapy against primary and distant tumors, along with efficient inhibition of lung metastasis. Our study not only offers a potent platform against tumors, but also provides a conceptually new approach to reinforce cancer immunotherapy.
Peripheral blood mononuclear cells (PBMC) were collected from ablated and nonablated woodchucks, labeled with carboxyfluorescein succinimidyl ester (CFSE) and cultured with immune-modulating drugs, including a small PD-L1 antagonist molecule (BMS-202) and three TLR7/8 agonists (DSR 6434, GS-9620, gardiquimod). Partial cryoablation augmented immune effects in both treated and remote untreated tumor microenvironments, as well as systemically, in woodchucks with HCC. Characterization of these mechanisms may enhance development of novel drug-device combinations for treatment of HCC.
The pH-responsive polymer equipped with the cell membrane anchoring peptide RKC is used as the carrier and further encapsulated with the near-infrared-activated semiconductor polymer photosensitizer YBS and a PD-1/PD-L1 complex small molecule inhibitor BMS-202...In vitro and in vivo studies have shown that this dual-pronged therapy stimulates a powerful antitumor immune response to suppress primary tumor progression and evokes long-term immune memory to inhibit tumor relapse and metastasis. This work provides an effective self-synergistic platform for PCa immunotherapy and a new idea for developing more biocompatible photo-controlled pyroptosis inducers.
7 months ago
Journal
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PD-L1 (Programmed death ligand 1) • PD-1 (Programmed cell death 1)
Upon evaluation of their immunological activities, the two compounds induced higher cytokines levels (IL-2, IL-6, and INF-γ) relative to BMS-202, 72 h post treatment of PBMCs of HCC patients. Thus, the discovered hits represent potential leads for the development of novel classes targeting the PD-L1 receptor as anti-hepatocellular carcinoma agents.
7 months ago
Journal • Checkpoint inhibition
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PD-L1 (Programmed death ligand 1) • PD-1 (Programmed cell death 1) • IL6 (Interleukin 6) • IL2 (Interleukin 2)
Exposing melanoma cells to BMS202-NDs led to a stronger than normal interaction between the hPBMCs and the melanoma cells, with significant anti-proliferative effects. We therefore conclude that melanoma therapy has the potential to be enhanced by non-classical T-cell Immune responses via immune checkpoint inhibitors delivered by nanodiamonds-based nanoparticles.
Our results indicate that early intervention against PD-L1 expression/activity could be a viable target for skin cancer photochemoprevention. Topical application of small molecule PD-L1 inhibitors such as BMS-202 may provide novel treatment options for populations at high risk for cSCC.