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1. Divergent Resistance Mechanisms to Immunotherapy Explain Responses in Different Skin Cancers

   https://doi.org/10.3390/cancers12102946  

   Dollinger, Emmanuel; Bergman, Daniel; Zhou, Peijie; Atwood, Scott X.; Nie, Qing (October 2020, Cancers)

   null (Ed.)

   The advent of immune checkpoint therapy for metastatic skin cancer has greatly improved patient survival. However, most skin cancer patients are refractory to checkpoint therapy, and furthermore, the intra-immune cell signaling driving response to checkpoint therapy remains uncharacterized. When comparing the immune transcriptome in the tumor microenvironment of melanoma and basal cell carcinoma (BCC), we found that the presence of memory B cells and macrophages negatively correlate in both cancers when stratifying patients by their response, with memory B cells more present in responders. Moreover, inhibitory immune signaling mostly decreases in melanoma responders and increases in BCC responders. We further explored the relationships between macrophages, B cells and response to checkpoint therapy by developing a stochastic differential equation model which qualitatively agrees with the data analysis. Our model predicts BCC to be more refractory to checkpoint therapy than melanoma and predicts the best qualitative ratio of memory B cells and macrophages for successful treatment. 

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2. Multiparatopic antibodies induce targeted downregulation of programmed death-ligand 1

   https://doi.org/10.1016/j.chembiol.2024.02.014  

   Ludwig, Seth D; Meksiriporn, Bunyarit; Tan, Jiacheng; Kureshi, Rakeeb; Mishra, Akhilesh; Kaeo, Kyle J; Zhu, Angela; Stavrakis, Georgia; Lee, Stephen J; Schodt, David J; et al (May 2024, Cell Chemical Biology)

   NA (Ed.)

   Programmed death-ligand 1 (PD-L1) drives inhibition of antigen-specific T cell responses through engage- ment of its receptor programmed death-1 (PD-1) on activated T cells. Overexpression of these immune checkpoint proteins in the tumor microenvironment has motivated the design of targeted antibodies that disrupt this interaction. Despite clinical success of these antibodies, response rates remain low, necessi- tating novel approaches to enhance performance. Here, we report the development of antibody fusion pro- teins that block immune checkpoint pathways through a distinct mechanism targeting molecular trafficking. By engaging multiple receptor epitopes on PD-L1, our engineered multiparatopic antibodies induce rapid clustering, internalization, and degradation in an epitope- and topology-dependent manner. The comple- mentary mechanisms of ligand blockade and receptor downregulation led to more durable immune cell acti- vation and dramatically reduced PD-L1 availability in mouse tumors. Collectively, these multiparatopic anti- bodies offer mechanistic insight into immune checkpoint protein trafficking and how it may be manipulated to reprogram immune outcomes. 

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3. An In Silico Glioblastoma Microenvironment Model Dissects the Immunological Mechanisms of Resistance to PD‐1 Checkpoint Blockade Immunotherapy

   https://doi.org/10.1002/smtd.202100197  

   Zhang, Zhuoyu; Liu, Lunan; Ma, Chao; Cui, Xin; Lam, Raymond H. W.; Chen, Weiqiang (April 2021, Small Methods)

   Abstract The PD‐1 immune checkpoint‐based therapy has emerged as a promising therapy strategy for treating the malignant brain tumor glioblastoma (GBM). However, patient response varies in clinical trials, mainly due to the tumor heterogeneity and immunological resistance in the tumor microenvironment. To further understand how mechanistically the niche interplay and competition drive anti‐PD‐1 resistance, an in silico model is established to quantitatively describe the biological rationale of critical GBM‐immune interactions, such as tumor growth and apoptosis, T cell activation and cytotoxicity, and tumor‐associated macrophage (TAM) mediated immunosuppression. Such an in silico experimentation and predictive model, based on the in vitro microfluidic chip‐measured end‐point data and patient‐specific immunological characteristics, allows for a comprehensive and dynamic analysis of multiple TAM‐associated immunosuppression mechanisms against the anti‐PD‐1 immunotherapy. The computational model demonstrates that the TAM‐associated immunosuppression varies in severity across different GBM subtypes, which results in distinct tumor responses. The prediction results indicate that a combination therapy by co‐targeting of PD‐1 checkpoint and TAM‐associated CSF‐1R signaling can enhance the immune responses of GBM patients, especially those patients with mesenchymal GBM who are irresponsive to the single anti‐PD‐1 therapy. The development of a patient‐specific in silico–in vitro GBM model will help navigate and personalize immunotherapies for GBM patients. 

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4. Nanotechnology‐enhanced radiotherapy and the abscopal effect: Current status and challenges of nanomaterial‐based radio‐immunotherapy

   https://doi.org/10.1002/wnan.1924  

   Viswanath, Dhushyanth; Park, Jeehun; Misra, Rahul; Pizzuti, Vincenzo J.; Shin, Sung‐Ho; Doh, Junsang; Won, You‐Yeon (August 2023, WIREs Nanomedicine and Nanobiotechnology)

   Abstract Rare but consistent reports of abscopal remission in patients challenge the notion that radiotherapy (RT) is a local treatment; radiation‐induced cancer cell death can trigger activation and recruitment of dendritic cells to the primary tumor site, which subsequently initiates systemic immune responses against metastatic lesions. Although this abscopal effect was initially considered an anomaly, combining RT with immune checkpoint inhibitor therapies has been shown to greatly improve the incidence of abscopal responses via modulation of the immunosuppressive tumor microenvironment. Preclinical studies have demonstrated that nanomaterials can further improve the reliability and potency of the abscopal effect for various different types of cancer by (1) altering the cell death process to be more immunogenic, (2) facilitating the capture and transfer of tumor antigens from the site of cancer cell death to antigen‐presenting cells, and (3) co‐delivering immune checkpoint inhibitors along with radio‐enhancing agents. Several unanswered questions remain concerning the exact mechanisms of action for nanomaterial‐enhanced RT and for its combination with immune checkpoint inhibition and other immunostimulatory treatments in clinically relevant settings. The purpose of this article is to summarize key recent developments in this field and also highlight knowledge gaps that exist in this field. An improved mechanistic understanding will be critical for clinical translation of nanomaterials for advanced radio‐immunotherapy. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease 

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5. Global stability and parameter analysis reinforce therapeutic targets of PD-L1-PD-1 and MDSCs for glioblastoma

   https://doi.org/10.1007/s00285-023-02027-y  

   Anderson, Hannah G.; Takacs, Gregory P.; Harris, Duane C.; Kuang, Yang; Harrison, Jeffrey K.; Stepien, Tracy L. (December 2023, Journal of Mathematical Biology)

   Abstract Glioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the approximate Bayesian computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended fourier amplitude sensitivity test. Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored. 

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