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T-cell exhaustion is a progressive loss of effector function and memory potential due to persistent antigen exposure, which occurs in chronic viral infections and cancer. Here we investigate the relation between gene expression and chromatin accessibility in CD8⁺ tumor-infiltrating lymphocytes (TILs) that recognize a model tumor antigen and have features of both activation and functional exhaustion. By filtering out accessible regions observed in bystander, nonexhausted TILs and in acutely restimulated CD8⁺ T cells, we define a pattern of chromatin accessibility specific for T-cell exhaustion, characterized by enrichment for consensus binding motifs for Nr4a and NFAT transcription factors. Anti–PD-L1 treatment of tumor-bearing mice results in cessation of tumor growth and partial rescue of cytokine production by the dysfunctional TILs, with only limited changes in gene expression and chromatin accessibility. Our studies provide a valuable resource for the molecular understanding of T-cell exhaustion in cancer and other inflammatory settings.

WEE1 plays an important role in the regulation of cell cycle G2/M checkpoints and DNA damage response (DDR). Inhibition of WEE1 can increase the instability of the genome and have anti–tumor effects in some solid tumors. However, it has certain limitations for multiple cancer cells from different lineages. Therefore, we consider the use of synthetic lethal interactions to enhance the therapeutic effect. Our experiments proved that WEE1 inhibitor (WEE1i) can activate the ataxia telangiectasia and RAD3‐related (ATR) pathway and that blockage of ATR dramatically sensitized the WEE1i‐induced cell death. The tumor‐selective synthetic lethality between bioavailable WEE1 and ATR inhibitors led to tumor remission in vivo. Mechanistically, the combination promoted the accumulation of cytosolic double‐strand DNA, which subsequently activated the stimulator of the interferon gene (STING) pathway and induced the production of type I interferon and CD8+ T cells, thereby inducing anti–tumor immunity. Furthermore, our study found that immune checkpoint programmed death‐ligand 1 is upregulated by the combination therapy, and blocking PD‐L1 further enhances the effect of the combination therapy. In summary, as an immunomodulator, the combination of WEE1i with ATR inhibitor (ATRi) and immune checkpoint blockers provides a potential new approach for cancer treatment. Combined application of WEE1i and ATRi in vivo and in vitro can inhibit tumor growth. Mechanistically, the combination promoted the accumulation of cytoplasmic dsDNA, which activated the STING‐TBK1‐IRF3 signal axis and induced the production of type I interferon, thereby inducing anti–tumor immunity. The effects of the combination were further enhanced by immune checkpoint PD‐L1 blockade.

Ziyun Cheng,1,2 Mohamadreza Amin,1 Mandy van Brakel,2 Andrea Sacchetti,3 Robbert Q Kim,4 Ann LB Seynhaeve,1 Reno Debets,2 Timo LM ten Hagen1 1Precision Medicine in Oncology (PrMiO) and Nanomedicine Innovation Center Erasmus (NICE), Department of Pathology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands; 2Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands; 3Department of Pathology, Erasmus MC, Rotterdam, the Netherlands; 4Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the NetherlandsCorrespondence: Timo LM ten Hagen, Precision Medicine in Oncology (PrMiO) and Nanomedicine Innovation Center Erasmus (NICE), Department of Pathology, Erasmus MC Cancer Institute, Erasmus MC, Molewaterplein 50, 3015, GE, Rotterdam, the Netherlands, Tel +31 0 614375863, Email t.l.m.tenhagen@erasmusmc.nlPurpose: Anti-programmed death ligand-1 monoclonal antibody (anti-PD-L1 mAb) therapy has demonstrated notable clinical success. However, efficacy is often limited by transient interactions at the tumor-immune interface, limiting sustained immune activation. To address this, we hypothesized that liposomal delivery of anti-PD-L1 mAbs could enhance therapeutic efficacy. Nanosystems may increase binding avidity and prolong cell-surface retention, and enable multivalent antibody presentation through conjugation of multiple antibodies onto a single liposome.Methods: In this study, we engineered multivalent anti-PD-L1 liposomes (anti-PD-L1 LPs) by conjugating FDA-approved anti-PD-L1 mAbs (atezolizumab) at varying densities onto a clinically relevant liposomal formulation. The biophysical properties, cellular interactions, and therapeutic potential of anti-PD-L1 LPs were evaluated using two melanoma cell line models (BLM and MZ2Mel43), employing multiple analytical techniques.Results: Our results demonstrated that high-density anti-PD-L1 LPs exhibited superior binding avidity, prolonged membrane retention, and reduced non-specific cellular interaction with PD-L1-expressing cells compared to both low-density and non-targeted LPs. Additionally, in 3D tumor spheroid models, high-density anti-PD-L1 LPs showed deeper penetration, suggesting improved tissue accessibility compared with low-density formulations. Moreover, compared to free antibodies, anti-PD-L1 LPs displayed a higher association rate (k_on) and a significantly lower dissociation rate (k_off), resulting in an overall improved (lower) dissociation constant (K_D). Functional assays confirmed that anti-PD-L1 LPs achieved superior PD-L1 blockade compared to free antibodies. Importantly, in co-cultures of human peripheral blood mononuclear cells and tumor cells, anti-PD-L1 LPs maintained immunomodulatory activity comparable to free anti-PD-L1 antibodies.Conclusion: This study highlights the critical role of ligand density in enhancing binding strength, tumor retention, and tissue penetration of the anti-PD-L1 LP system. Our nanosystem offers a promising improvement over conventional anti-PD-L1 mAbs, supporting the broader application of this modular liposomal platform to other therapeutic antibodies in melanoma and other solid tumors.Plain Language Summary: Current limitations and our approachCancer immunotherapy drugs like anti-PD-L1 antibodies help the immune system fight cancer, but they often do not stay in tumors long enough to work effectively. To improve this, we developed nanoscale lipid-based carriers, like tiny fat bubbles (called liposomes) densely coated with anti-PD-L1 antibodies. These engineered liposomes bind to tumors more effectively, stay longer, and deliver treatment more precisely than regular antibodies.Key discoveriesWe discovered that packing more drugs onto each tiny carrier makes them stick to tumors better and last longer. Also, how we deliver these drugs matters too—the carrier-delivered versions bind to tumors more effectively than regular antibody drugs. Importantly, in controlled lab tests with cells, these engineered antibodies work just as powerfully as regular immunotherapy—proving we have created a delivery system without sacrificing cancer-fighting strength.Conclusion and potential benefitsThis research introduces an innovative approach to cancer immunotherapy delivery using antibody-coated liposomes. By enhancing tumor targeting and retention while minimizing accumulation in healthy tissues, this method could improve treatment effectiveness while reducing side effects. The platform offers three key advantages: patients may require fewer treatment sessions with more durable results, clinicians gain enhanced options for treating melanoma and solid tumors, and researchers can extend this adaptable platform to other cancer therapies.Future directionsOur immediate focus will be on validating these findings in animal models and expanding the technology to other immunotherapies. The use of clinically approved components positions this approach for potential rapid translation to human trials, pending successful preclinical results. Keywords: cancer immunotherapy, melanoma, immune checkpoint inhibitors, liposomes, anti-PD-L1 mAb, targeted drug delivery

Programmed cell death-1 (PD-1) has demonstrated impressive clinical outcomes in several malignancies, but its therapeutic efficacy in the majority of colorectal cancers is still low. Therefore, methods to improve its therapeutic efficacy in colorectal cancer (CRC) patients need further investigation. Here, we demonstrate that immunogenic chemotherapeutic agents trigger the induction of tumor PD-L1 expression in vitro and in vivo, a fact which was validated in metastatic CRC patients who received preoperatively neoadjuvant chemotherapy (neoCT) treatment, suggesting that tumor PD-L1 upregulation by chemotherapeutic regimen is more feasible via PD-1/PD-L1 immunotherapy. However, we found that the epigenetic control of tumor PD-L1 via DNA methyltransferase 1 (DNMT1) significantly influenced the response to chemotherapy. We demonstrate that decitabine (DAC) induces DNA hypomethylation, which not only directly enhances tumor PD-L1 expression but also increases the expression of immune-related genes and intratumoral T cell infiltration in vitro and in vivo. DAC was found to profoundly enhance the therapeutic efficacy of PD-L1 immunotherapy to inhibit tumor growth and prolong survival in vivo. Therefore, it can be seen that DAC remodels the tumor microenvironment to improve the effect of PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger anti-cancer immune responses, providing potential clinical benefits to CRC patients in the future.

Background: Several immunotherapy (IT) agents are FDA approved for treatment of melanoma and non-small-cell lung cancer (NSCLC). The addition of stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT) to immunotherapy looks promising. A systematic review was conducted to evaluate the possible synergistic effects of immune checkpoints inhibitors (ICIs) and stereotactic radiation therapy in melanoma and NSCLC. Materials and methods: Pubmed databases from January 2010 to December 2020 were reviewed to identify English language studies reporting control of local and abscopal effect of the combination of ICI-SBRT/SRS in metastatic NSCLC and melanoma cancer. The inclusion criteria were followed according to PICO criteria. Results: Thirty-nine articles were included of the 2141 initial results. The reported rates for local control were 16.5–100% and 40–94% in brain and extracerebral metastases, respectively. Distant/abscopal response rates were 1–45% in extracerebral metastases. Abscopal effect could not be evaluated in brain metastases because it was not reported in studies. Treatments were well tolerated with few grade 4 toxicities and no grade 5. Conclusions: The combined treatment of ICI-SBRT/SRS achieves high local control and non-negligible abscopal response in patients with extracerebral metastases, with its benefit in cerebral metastases being more controversial. Clinical trials are needed to better characterize the potential synergism.

Background Metastatic castration‐resistant prostate cancer (mCRPC) remains fatal and incurable, despite a variety of treatments that can delay disease progression and prolong life. Immune checkpoint therapy is a promising treatment. However, emerging evidence suggests that exosomal programmed necrosis ligand 1 (PD‐L1) directly binds to PD‐1 on the surface of T cells in the drain lineage lymph nodes or neutralizes administered PD‐L1 antibodies, resulting in poor response to anti‐PD‐L1 therapy in mCRPC. Materials and Methods Western blotting and immunofluorescence were performed to compare PD‐L1 levels in exosomes derived from different prostate cancer cells. PC3 cells were subcutaneously injected into nude mice, and then ELISA assay was used to detect human specific PD‐L1 in exosomes purified from mouse serum. The function of CD8+ T cells was detected by T cell mediated tumor cell killing assay and FACS analysis. A subcutaneous xenograft model was established using mouse prostate cancer cell RM1, exosomes with or without PD‐L1 were injected every 3 days, and then tumor size and weight were analyzed to evaluate the effect of exosomal PD‐L1. Results Herein, we found that exosomal‐PD‐L1 was taken up by tumor cells expressing low levels of PD‐L1, thereby protecting them from T‐cell killing. Higher levels of PD‐L1 were detected in exosomes derived from the highly malignant prostate cancer PC3 and DU145 cell lines. Moreover, exosomal PD‐L1 was taken up by the PD‐L1‐low‐expressing LNCaP cell line and inhibited the killing function of CD8‐T cells on tumor cells. The growth rate of RM1‐derived subcutaneous tumors was decreased after knockdown of PD‐L1 in tumor cells, whereas the growth rate recovered following exosomal PD‐L1 tail vein injection. Furthermore, in the serum of mice with PCa subcutaneous tumors, PD‐L1 was mainly present on exosomes. Conclusion In summary, tumor cells share PD‐L1 synergistically against T cells through exosomes. Inhibition of exosome secretion or prevention of PD‐L1 sorting into exosomes may improve the therapeutic response of prostate tumors to anti‐PD‐L1 therapy.

ObjectiveIn the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models.DesignWe analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and OPNknockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC.ResultsThe numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPNhigh tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8+ T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC.ConclusionsOPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.

Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in situ, as it is “curable” at this stage. However, after metastasis, it is difficult to treat and the five-year survival is only 25%. In recent years, a better understanding of the etiology of melanoma and its progression has made it possible for the development of targeted therapeutics, such as vemurafenib and immunotherapies, to treat advanced melanomas. In this review, we focus on the molecular mechanisms that mediate melanoma development and progression, with a special focus on the immune evasion strategies utilized by melanomas, to evade host immune surveillances. The proposed mechanism of action and the roles of immunotherapeutic agents, ipilimumab, nivolumab, pembrolizumab, and atezolizumab, adoptive T- cell therapy plus T-VEC in the treatment of advanced melanoma are discussed. In this review, we implore that a better understanding of the steps that mediate melanoma onset and progression, immune evasion strategies exploited by these tumor cells, and the identification of biomarkers to predict treatment response are critical in the design of improved strategies to improve clinical outcomes for patients with this deadly disease.

Recent progress in tumor immunology has revealed that tumors generate immunologically restrained milieu during the process of their growth, which facilitates the escape of tumors from host immune systems. Immune checkpoint molecules, which transduce co‐inhibitory signals to immuno‐competent cells, are one of the most important components conferring the immunosuppressive capacity in the tumor microenvironment. Cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) and programmed cell death‐1 (PD‐1) are typical immune checkpoint molecules intimately involved in the suppression of anti‐tumor immunity. Antibodies against those molecules have been developed, such as ipilimumab (anti‐CTLA‐4 antibody), nivolumab and pembrolizumab (anti‐PD‐1 antibody), and have been approved by regulatory agencies and used in some countries. Treatment with these antibodies demonstrates previously unobserved clinical efficacies superior to the conventional therapies. In this review, we first discuss the escape mechanisms of cancer from host immune systems, and then focus on the recent advances in immune checkpoint blockade therapy and on the new findings of related immune reactions, aiming to provide a better understanding of the novel cancer immunotherapies. The aim of cancer immunotherapies is to make the balance of the host immunity biased toward stimulation‐dominant side while the balance is strikingly biased toward inhibition‐dominant side in the tumor microenvironment. In conventional immunotherapy, the immunological balance is tried to be shifted by “putting the weights on the stimulatory side”. In immune checkpoint blockade therapy, the balance is tried to be shifted by “decreasing or removing the weights from the inhibitory side”.

Background. Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)–specific immunity and increase clearance of HIV-1–expressing cells. Methods. We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1–infected adults aged ≥18 to ≤70 years on suppressive antiretroviral therapy with CD4+ counts ≥350 cells/μL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion. Results. Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559. Conclusions. In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1–infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1–specific immunity in a subset of participants. Clinical Trials Registration. NCT02028403.