Preclinical application of a CD155 targeting chimeric antigen receptor T cell therapy for digestive system cancers
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Targeting of TAMs: can we be more clever than cancer cells?
With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.
The ENaC taste receptor’s perceived mechanism of mushroom salty peptides revealed by molecular interaction analysis
The ENaC receptor acts as a taste receptor to recognize and perceive salty substances. This study explored the mechanisms by which the ENaC taste receptor recognizes and binds mushroom-derived salty peptides using molecular interaction and molecular simulation. The three subunits α, β, and γ of the ENaC taste receptor (SCNN1α, SCNN1β, and SCNN1γ) showed different recognition characteristics for the salty peptide. The salty peptide binding to the SCNN1α receptor was an entropy-driven reaction, while to SCNN1β and SCNN1γ was an enthalpy-driven reaction. With the salty peptide spatial resistance increasing, salty peptides bind to the ENaC taste receptor shifted from receptor pockets binding to receptor surface binding, with salty octapeptide ESPERPFL preferentially binding to amino acid residues in the receptor pockets 2, 3, and 4, salty nonapeptide KSWDDFFTR and decapeptide RIEDNLVIIR binding to amino acid residues in the pockets 2, 4 and on the surface of the receptor, and salty undecapeptide GQEDYDRLRPL preferentially binding to the atoms on the surface of the receptor. Receptor extracellular arginine, glutamate, aspartate, and lysine residues were the critical amino acid residues recognized to bind salty peptides. The salty peptide-ENaC receptor binding complex was stable around 0.3 nm, and the tight and multisite binding was the main reason the ENaC receptor sensed the salty peptide, enabling it to exert its taste effect. This research can provide a theoretical basis for understanding the taste properties of salty peptides recognized and perceived by the ENaC taste receptor.
The guided fire from within: intratumoral administration of mRNA-based vaccines to mobilize memory immunity and direct immune responses against pathogen to target solid tumors
We investigated a novel cancer immunotherapy strategy that effectively suppresses tumor growth in multiple solid tumor models and significantly extends the lifespan of tumor-bearing mice by introducing pathogen antigens into tumors via mRNA-lipid nanoparticles. The pre-existing immunity against the pathogen antigen can significantly enhance the efficacy of this approach. In mice previously immunized with BNT162b2, an mRNA-based COVID-19 vaccine encoding the spike protein of the SARS-CoV-2 virus, intratumoral injections of the same vaccine efficiently tagged the tumor cells with mRNA-expressed spike protein. This action rapidly mobilized the pre-existing memory immunity against SARS-CoV-2 to kill the cancer cells displaying the spike protein, while concurrently reprogramming the tumor microenvironment (TME) by attracting immune cells. The partial elimination of tumor cells in a normalized TME further triggered extensive tumor antigen-specific T cell responses through antigen spreading, eventually resulting in potent and systemic tumor-targeting immune responses. Moreover, combining BNT162b2 treatment with anti-PD-L1 therapy yielded a more substantial therapeutic impact, even in “cold tumor” types that are typically less responsive to treatment. Given that the majority of the global population has acquired memory immunity against various pathogens through infection or vaccination, we believe that, in addition to utilizing the widely held immune memory against SARS-CoV-2 via COVID-19 vaccine, mRNA vaccines against other pathogens, such as Hepatitis B Virus (HBV), Common Human Coronaviruses (HCoVs), and the influenza virus, could be rapidly transitioned into clinical use and holds great promise in treating different types of cancer. The extensive selection of pathogen antigens expands therapeutic opportunities and may also overcome potential drug resistance.
A mathematical framework for comparison of intermittent versus continuous adaptive chemotherapy dosing in cancer
Chemotherapy resistance in cancer remains a barrier to curative therapy in advanced disease. Dosing of chemotherapy is often chosen based on the maximum tolerated dosing principle; drugs that are more toxic to normal tissue are typically given in on-off cycles, whereas those with little toxicity are dosed daily. When intratumoral cell-cell competition between sensitive and resistant cells drives chemotherapy resistance development, it has been proposed that adaptive chemotherapy dosing regimens, whereby a drug is given intermittently at a fixed-dose or continuously at a variable dose based on tumor size, may lengthen progression-free survival over traditional dosing. Indeed, in mathematical models using modified Lotka-Volterra systems to study dose timing, rapid competitive release of the resistant population and tumor outgrowth is apparent when cytotoxic chemotherapy is maximally dosed. This effect is ameliorated with continuous (dose modulation) or intermittent (dose skipping) adaptive therapy in mathematical models and experimentally, however, direct comparison between these two modalities has been limited. Here, we develop a mathematical framework to formally analyze intermittent adaptive therapy in the context of bang-bang control theory. We prove that continuous adaptive therapy is superior to intermittent adaptive therapy in its robustness to uncertainty in initial conditions, time to disease progression, and cumulative toxicity. We additionally show that under certain conditions, resistant population extinction is possible under adaptive therapy or fixed-dose continuous therapy. Here, continuous fixed-dose therapy is more robust to uncertainty in initial conditions than adaptive therapy, suggesting an advantage of traditional dosing paradigms.
Exploring Clec9a in dendritic cell-based tumor immunotherapy for molecular insights and therapeutic potentials
The pivotal role of type 1 conventional dendritic cells (cDC1s) in the field of dendritic cell (DC)-based tumor immunotherapies has been gaining increasing recognition due to their superior antigen cross-presentation abilities and essential role in modulating immune responses. This review specifically highlights the C-type lectin receptor family 9 member A (Clec9a or DNGR-1), which is exclusively expressed on cDC1s and plays a pivotal role in augmenting antigen cross-presentation and cytotoxic T lymphocyte (CTL) responses while simultaneously mitigating off-target effects. These effects include the enhancement of the cDC1s cross-presentation, reducing autoimmune responses and systemic inflammation, as well as preventing the non-specific activation of other immune cells. Consequently, these actions may contribute to reduced toxicity and enhanced treatment efficacy in immunotherapy. The exceptional ability of Clec9a to cross-present dead cell-associated antigens and enhance both humoral and CTL responses makes it an optimal receptor for DC-based strategies aimed at strengthening antitumor immunity. This review provides a comprehensive overview of the molecular characterization, expression, and signaling mechanisms of Clec9a. Furthermore, it discusses the role of Clec9a in the induction and functional activation of Clec9a+ cDC1s, with a particular focus on addressing the challenges related to off-target effects and immune tolerance in the development of tumor vaccines. Additionally, this review explores the potential of Clec9a-targeted approaches to enhance the immunogenicity of tumor vaccines and addresses the utilization of Clec9a as a delivery target for specific agonists (such as STING agonists and αGC) to enhance their therapeutic effects. This novel approach leverages Clec9a’s capacity to improve the precision and efficacy of these immunomodulatory molecules in tumor treatment. In summary, this review presents compelling evidence positioning Clec9a as a promising target for DC-based tumor immunotherapy, capable of enhancing the efficacy of vaccines and immune responses while minimizing adverse effects.
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