Shasha Liu

Tumor immunotherapy is a promising therapeutic strategy for patients with advanced cancers. T cells are key mediators of antitumor function that specifically recognize and react to tumor-expressing antigens and have proven critical for cancer immunotherapy. However, T cells are not as effective against cancer as expected. This is partly because T cells enter a dysfunctional or exhausted state, which is characterized by sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. T cell dysfunction induces the out of control of tumors. Recently, T cell dysfunction has been investigated in many experimental and clinical settings. The molecular definition of T cell dysfunction and the underlying causes of the T cell dysfunction has been advanced regardless of the fact that the pathways involved are not well elucidated, which proposing promising therapeutic opportunities in clinic. In this review, we will discuss the recent advances in the molecular mechanisms that affect TME and induce T cell dysfunction, and the development of promising immunotherapies to counteract the mechanisms of tumor-induced T cell dysfunction. Better understanding these underlying mechanisms may lead to new strategies to improve the clinical outcome of patients with cancer.

Green and yellow-emitting 1,6- and 1,8-bis(phenylethynyl) pyrenes (dyes 7, 8, 9, and 10) with different intramolecular charge transfer (ICT) feature were synthesized and the effect of ICT on the photophysical properties of these derivatives were studied by UV-vis absorption spectra, fluorescence emission spectra, and DFT/TDDFT calculations. For the dyes with electron-pushing group (e.g., -dimethylamino, dye 8 and dye 10), structureless and solvent polarity-sensitive fluorescence emission spectra were observed. Conversely, dye with electron-withdrawing group (e.g., -CN, dye 7) shows structured and solvent polarity-independent emission spectra. OFF-ON fluorescent thiol probes 11 and 12 with 2,4-dinitrobenzenesulfonyl protected ethynylpyrene fluorophore were designed based on DFT/TDDFT calculations, which predicts dark state (S(1)) for these thiol probes (e.g., oscillator strength f = 0.0086 for S(1)<--S(0) transition of the probe 11). This dark state is induced by the ICT effect with ethynylated pyrene fluorophore as electron donor and 2,4-dinitrobenzenesulfonyl unit as electron acceptor. Cleavage of the 2,4-dinitrobenzenesulfonyl unit by thiol releases the free fluorophore, for which the lowest-lying excited state S(1) is no longer a dark state, but an emissive state (f = 0.9776 for S(1)<--S(0) transition). These theoretical predictions on the photophysical properties of the molecular probes were fully proved by experimental results. Our results demonstrated that the fluorescence OFF-ON switching of this kind of thiol probe is due to the termination of the ICT effect (which quenches the emission, by a dark S(1) state) by cleavage of the 2,4-dinitrobenzenesulfonyl unit (as acceptor of ICT effect) with thiols, not the re-establishment of the D-pi-A feature of the fluorophore. These investigation on the pyrene derived green-emitting fluorophores and the DFT/TDDFT calculation aided probe design suggest that future application of these results may prove useful toward the rational design of fluorophores or fluorescent probes with predetermined photophysical properties.

Ru(Phen)(bpy)2 (1) and its new derivatives (2–5) with pyrenyl or ethynylated pyrene and phenyl units appended to the 3-position of the phenanthroline (Phen) ligand were prepared and these complexes generate long-lived room temperature phosphorescence in the red and near IR range (600–800 nm). The photophysical properties of these complexes were investigated by UV-Vis absorption, luminescence emission, transient absorption spectra and DFT/TDDFT calculations. We found the luminescence lifetime (τ)can be drastically extended by ligand modification (increased up to 140-fold), e.g. τ = 58.4 μs for complex 3 (with pyrenyl ethynylene appendents) was found, compared to τ = 0.4 μs for the reference complex 1. Ethynylated phenyl appendents alter the τ also (complex 2, τ = 2.4 μs). With pyrenyl appendents (4 and 5), lifetimes of 2.5 μs and 9.2 μs were observed. We proposed three different mechanisms for the lifetime extension of 2, 3, 4 and 5. For 2, the stabilization of the 3MLCT state by π-conjugation is responsible for the extension of the lifetime. For 3, the emissive state was assigned as an intra-ligand (IL) long-lived 3π–π* state (3IL/3LLCT, intraligand or ligand-to-ligand charge transfer), whereas a C–C single bond linker results in a triplet state equilibrium between 3MLCT state and the pyrene localized 3π–π* triplet state (3IL, e.g.4 and 5). DFT/TDDFT calculations support the assignment of the emissive states. The effects of the lifetime extension on the oxygen sensing properties of these complexes were studied in both solution and polymer films. With tuning the emissive states, and thus extension of the luminescence lifetimes, the luminescent O2 sensing sensitivity of the complexes can be improved by ca. 77-fold in solution (I0/I100 = 1438 for complex 3, vs. I0/I100 = 18.5 for complex 1). In IMPES-C polymer films, the apparent quenching constant KSVapp is improved by 150-fold from 0.0023 Torr−1 (complex 1) to 0.35 Torr−1 (complex 3). The KSVapp value of complex 3 is even higher than that of PtOEP under similar conditions (0.15 Torr−1).