The emergence of immune checkpoint blockade to activate host T cells to attack tumor cells has revolutionized the cancer treatment landscape over the past decade. However, sustained response has only ...been achieved in a small proportion of patients. This can be attributed to physiological barriers, such as T-cell heterogeneity and immunosuppressive tumor microenvironments. To this can be added obstacles intrinsic to traditional antibody-driven blockade methods, including the inability to inhibit checkpoint translocation from cytoplasm, systemic immune toxicity, and “bite back” effect on T cells. Using non-small cell lung cancer (NSCLC) as the cancer model, here we report an unconventional, yet powerful, tumor-targeted checkpoint blocking strategy by RNAi nanoengineering for T-cell-independent cancer therapy. Unlike antibodies, such nanoblocker silences both membranous and cytoplasmic PD-L1 in cancer cells, thus eliminating the binding step. Moreover, it is demonstrated that silencing of PD-L1 by the nanoblocker can cause the direct programmed cell death of NSCLC H460 cells, without the need of T-cell intervention. In vivo results from xenograft tumor models further demonstrate that tumor-homing peptide modification enables the nanoblocker to accumulate in the tumor tissue, downregulate the PD-L1 expression, and inhibit the tumor growth more efficiently than the nontargeted group. These findings may offer an effective means toward overcoming barriers against traditional checkpoint blockade and provide different insights into the molecular mechanism(s) underlying immunotherapy.
Immune checkpoint blockade therapy has become a major weapon in fighting cancer. Antibody drugs, such as anti-PD-1 and anti-PD-L1, demonstrate obvious advantages such as broad applicability across ...cancer types and durable clinical response when treatment is effective. However, the overall response rates are still unsatisfying, especially for cancers with low mutational burden. Moreover, adverse effects, such as autoimmune symptoms and tumor hyperprogression, present a significant downside in some clinical applications. These challenges reflect the urgent need to fully understand the basic biology of immune checkpoints. In this review, we discuss regulation of immune checkpoint signaling at multiple levels to provide an overview of our current understanding of checkpoint biology. Topics include the regulation of surface expression levels for known immune checkpoint proteins via surface delivery, internalization, recycling, and degradation. Upon reaching the surface, checkpoints engage in both conventional trans and also cis interactions with ligands to induce signaling and regulate immune responses. Novel therapeutic strategies targeting these pathways in addition to classical checkpoint blockade have recently emerged and been tested in preclinical models, providing new avenues for developing next-generation immunotherapies.
Despite the considerable potential of immune checkpoint blockade (ICB) therapy in treating various cancer types, it faces several challenges, of which the constrained objective response rate and ...relatively short duration of response observed in patients with cancer are the most important. This study introduces an injectable temperature-sensitive hydrogel, Pluronic F-127 (PF-127)@MnCl2/ alginate microspheres (ALG-MS)@MgCl2, that enhances the therapeutic efficacy of programmed cell death-ligand 1 (PD-L1) in cancer cells. The hydrogel material used in this study facilitated the rapid release of a significant amount of manganese ions (Mn2+) and the gradual and sustained release of magnesium ions (Mg2+) within the tumor microenvironment. This staged release profile promotes an immune microenvironment conducive to the cytotoxicity of CD8+ T cells and natural killer cells, thereby enhancing the efficacy of ICB therapy. Furthermore, the PF-127@MnCl2/ALG-MS@MgCl2 composite hydrogel exhibits the ability to convert drug-resistant tumor (“cold tumor”) with a low PD-L1 response to a “hot tumor” with a high PD-L1 response. In summary, the PF-127@MnCl2/ALG-MS@MgCl2 hydrogel manipulates the immune microenvironment through the precise discharge of Mg2+ and Mn2+, thus, augmenting the efficacy of ICB therapy.
Enhancing the effectiveness of immune checkpoint blockade therapy can be achieved by manipulating the immune microenvironment by utilizing PF-127@MnCl2/ALG-MS@MgCl2 injectable temperature-sensitive hydrogel. Display omitted
Therapeutically manipulating the stimulator of interferon genes (STING) pathway has promising potential for enhancing antitumor immunity. Agonists of this pathway (STING agonists) are being evaluated ...in clinical trials. Loading the STING agonists into lipid nanoparticles (LNPs) increases their safety and efficacy. We previously developed STING agonists loaded LNPs consisting of the ionizable lipid YSK12-C4 (YSK12-LNPs), which showed significant antitumor effects. However, it is largely unclear how the in vivo fate of STING agonists loaded LNPs affects the antitumor immune responses. In this study, we compared the YSK12-LNPs with LNPs composed of DLin-MC3-DMA (MC3-LNPs) showing different in vivo fates. Biodistribution and flow cytometry analyses of mouse tissues revealed that the MC3-LNPs delivered higher amounts of STING agonists to the liver than the YSK12-LNPs. Additionally, significantly more liver leukocytes internalized the MC3-LNPs than the YSK12-LNPs. In contrast, the YSK12-LNPs delivered higher amounts of STING agonists to the liver leukocytes than the MC3-LNPs, leading to the effective induction of innate immunity and inflammation in the tumors. However, the antitumor effects in the B16-F10 lung metastasis and CT26 tumor models were comparable. Interestingly, flow cytometry analyses suggested that the YSK12-LNPs were more likely to activate natural killer cells and M1 macrophages, while the MC3-LNPs were more likely to activate CD8+ T cells. Our data suggest that different antitumor immune response mechanisms may operate depending on the characteristics and distribution of the LNPs.
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•The LNP in vivo fate influences the immune responses of the STING agonist.•YSK12-LNPs were more likely to activate natural killer cells and M1 macrophages.•MC3-LNPs were more likely to activate CD8+ T cells.•The YSK12-LNPs and MC3-LNPs had comparable antitumor effects.
Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8+ T cells ...remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8+ T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8+ T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8+ T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8+ T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8+ T cell exhaustion and could be targeted to potentiate cancer immunotherapy.
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•Osr2 is selectively induced in activated CD8+ T cells in response to mechanical stress•Mechanical stress augments CD8+ T cell exhaustion via the Piezo1/CaMKII/CREB/Osr2 axis•Osr2 specifically attenuates the functionality of terminally exhausted CD8+ T cells•Targeting Osr2 signaling enhances T cell-mediated immunotherapies against solid tumors
Biomechanical stress drives CD8+ T cell exhaustion program in solid tumors via a signaling cascade centered on the transcription factor Osr2. Intervention in this signaling pathway reverses CD8+ T cell exhaustion and enhances their anti-tumor efficacy.
The stimulator of interferon genes (STING) connects the innate and adaptive immune system and plays a significant role in antitumor immunity. Over the past decades, endogenous and CDN-derived STING ...agonists have been a hot topic in the research of cancer immunotherapies. However, these STING agonists are either in infancy with limited biological effects or have failed in clinical trials. In 2020, a non-nucleotide STING agonist MSA-2 was identified, which exhibited satisfactory antitumor effects in animal studies and is amenable to oral administration. Due to its distinctive binding mode and enhanced bioavailability, there have been accumulating interests and an array of studies on MSA-2 and its derivatives, spanning its structure-activity relationship, delivery systems, applications in combination therapies, etc. Here, we provide a comprehensive review of MSA-2 and interventional strategies based on this family of STING agonists to help more researchers extend the investigation on MSA-2 in the future.
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Cancer Immunotherapy
In article number 2306248, Yao‐Xin Lin, Hao Wang, and co‐workers report the polymer peptide assembled nanorobot as an elegant tool for CpG delivery. These nanorobots induce ...autophagy‐mediated cell death through structural deformation, resulting in enhanced efficacy of immunotherapy. This innovative approach provides a robust strategy in reinvigorating antitumor immunity.
Reversing the aggravated immunosuppression hence overgrowth of colorectal cancer (CRC) caused by the gut inflammation and microbiota dysbiosis is pivotal for effective CRC therapy and metastasis ...inhibition. However, the low delivery efficiency and severe dose-limiting off-target toxicities caused by unsatisfied drug delivery systems remain the major obstacles in precisely modulating gut inflammation and microbiota in CRC therapy. Herein, a multifunctional oral dextran-aspirin nanomedicine (P3C-Asp) was utilized for oral treatment of primary CRC, as it could release salicylic acid (SA) while scavenging reactive oxygen species (ROS) and held great potential in modulating gut microbiota with prebiotic (dextran). Oral P3C-Asp retained in CRC tissues for over 12 h and significantly increased SA accumulation in CRC tissues over free aspirin (10.8-fold at 24 h). The enhanced SA accumulation and ROS scavenging of P3C-Asp cooperatively induced more potent inflammation relief over free aspirin, characterized as lower level of cyclooxygenase-2 and immunosuppressive cytokines. Remarkably, P3C-Asp promoted the microbiota homeostasis and notably increased the relative abundance of strengthening systemic anti-cancer immune response associated microbiota, especially lactobacillus and Akkermansia to 6.66- and 103- fold over the control group. Additionally, a demonstrable reduction in pathogens associated microbiota (among 96% to 79%) including Bacteroides could be detected. In line with our findings, inflammation relief along with enhanced abundance of lactobacillus was positively correlated with CRC inhibition. In primary CRC model, P3C-Asp achieved 2.1-fold tumor suppression rate over free aspirin, with an overall tumor suppression rate of 85%. Moreover, P3C-Asp cooperated with αPD-L1 further reduced the tumor weight of each mouse and extended the median survival of mice by 29 days over αPD-L1 alone. This study unravels the synergistic effect of gut inflammation and microbiota modulation in primary CRC treatment, and unlocks an unconventional route for immune regulation in TME with oral nanomedicine.
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•P3C-Asp is constructed with aspirin, ROS scavenging moiety, and prebiotic for primary colorectal cancer treatment.•P3C-Asp can simultaneously improve tumor microenvironment and enhance probiotics to reinvigorate antitumor immune responses.•The noninvasive and functional-rich P3C-Asp provides a promising candidate for gastrointestinal diseases treatment.
Dendritic cells (DCs) are the main professional antigen-presenting cells for induction of T-cell adaptive responses. Cancer cells express tumor antigens, including neoantigens generated by ...nonsynonymous mutations, but are poor for antigen presentation and for providing costimulatory signals for T-cell priming. Mounting evidence suggests that antigen transfer to DCs and their surrogate presentation on major histocompatibility complex class I and II molecules together with costimulatory signals is paramount for induction of viral and cancer immunity. Of the great diversity of DCs, BATF3/IRF8-dependent conventional DCs type 1 (cDC1) excel at cross-presentation of tumor cell-associated antigens. Location of cDC1s in the tumor correlates with improved infiltration by CD8+ T cells and tumor-specific T-cell immunity. Indeed, cDC1s are crucial for antitumor efficacy using checkpoint inhibitors and anti-CD137 agonist monoclonal antibodies in mouse models. Enhancement and exploitation of T-cell cross-priming by cDC1s offer opportunities for improved cancer immunotherapy, including in vivo targeting of tumor antigens to internalizing receptors on cDC1s and strategies to increase their numbers, activation and priming capacity within tumors and tumor-draining lymph nodes.
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