skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: In Situ Dendritic Cell Recruitment and T Cell Activation for Cancer Immunotherapy
Cancer immunotherapy has shifted the paradigm for cancer treatment in the past decade, but new immunotherapies enabling the effective treatment of solid tumors are still greatly demanded. Here we report a pore-forming hydrogel-based immunotherapy that enables simultaneous recruitment of dendritic cells and in situ activation of T cells, for reshaping the immunosuppressive tumor microenvironment and amplifying cytotoxic T lymphocyte response. The injectable pore-forming hydrogel composed of porogen-dispersed alginate network can form a macroporous structure upon injection into mice, and enables controlled release of granulocyte-macrophage colony-stimulating factor (GM-CSF), a chemoattractant for recruiting dendritic cells, and epacadostat, an inhibitor of indoleamine 2, 3-dioxygenase for activating T cells. We show that gels loaded with GM-CSF and epacadostat, after peritumoral injection, can recruit massive dendritic cells in situ and activate effector T cells in the tumor tissues, resulting in enhanced frequency and activation status of dendritic cells, reduced numbers of regulatory T (Treg) cells, and increased CD8 + /Treg ratios in the tumor microenvironment. This hydrogel-based immunotherapy holds great promise for treating poorly-immunogenic solid tumors.  more » « less
Award ID(s):
2143673
PAR ID:
10389217
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Frontiers in Pharmacology
Volume:
13
ISSN:
1663-9812
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; ; ; ; (, Biofabrication)
    Abstract Immunotherapy has revolutionized cancer treatment with the advent of advanced cell engineering techniques aimed at targeted therapy with reduced systemic toxicity. However, understanding the underlying immune–cancer interactions require development of advanced three-dimensional (3D) models of human tissues. In this study, we fabricated 3D tumor models with increasing complexity to study the cytotoxic responses of CD8 + T cells, genetically engineered to express mucosal-associated invariant T (MAIT) cell receptors, towards MDA-MB-231 breast cancer cells. Homotypic MDA-MB-231 and heterotypic MDA-MB-231/human dermal fibroblast tumor spheroids were primed with precursor MAIT cell ligand 5-amino-6-D-ribitylaminouracil (5-ARU). Engineered T cells effectively eliminated tumors after a 3 d culture period, demonstrating that the engineered T cell receptor recognized major histocompatibility complex class I-related (MR1) protein expressing tumor cells in the presence of 5-ARU. Tumor cell killing efficiency of engineered T cells were also assessed by encapsulating these cells in fibrin, mimicking a tumor extracellular matrix microenvironment. Expression of proinflammatory cytokines such as interferon gamma, interleukin-13, CCL-3 indicated immune cell activation in all tumor models, post immunotherapy. Further, in corroborating the cytotoxic activity, we found that granzymes A and B were also upregulated, in homotypic as well as heterotypic tumors. Finally, a 3D bioprinted tumor model was employed to study the effect of localization of T cells with respect to tumors. T cells bioprinted proximal to the tumor had reduced invasion index and increased cytokine secretion, which indicated a paracrine mode of immune–cancer interaction. Development of 3D tumor-T cell platforms may enable studying the complex immune–cancer interactions and engineering MAIT cells for cell-based cancer immunotherapies. 
    more » « less
  2. ; ; ; ; (, Frontiers in Immunology)
    Chemoimmunotherapy that utilizes the immunomodulatory effect of chemotherapeutics has shown great promise for treating poorly immunogenic solid tumors. However, there remains a significant room for improving the synergy between chemotherapy and immunotherapy, including the efficient, concurrent delivery of chemotherapeutics and immunomodulators into tumors. Here, we report the use of metabolic glycan labeling to facilitate cancer-targeted delivery of liposomal chemoimmunotherapy. 4T1 triple-negative breast cancer cells can be metabolically labeled with azido groups for subsequently targeted conjugation of dibenzocycoloctyne (DBCO)-bearing liposomes loaded with doxorubicin and imiquimod (R837) adjuvant via efficient click chemistry. The encased doxorubicin can induce the immunogenic death of cancer cells and upregulate the expression of CD47 and calreticulin on the surface of cancer cells, while R837 can activate dendritic cells for enhanced processing and presentation of tumor antigens. Targeted delivery of liposomes encapsulating doxorubicin and R837 to 4T1 tumors, enabled by metabolic glycan labeling and click chemistry, showed the promise to reshape the immunosuppressive tumor microenvironment of solid tumors. This cancer-targetable liposomal chemoimmunotherapy could provide a new approach to improving conventional chemotherapy. 
    more » « less
  3. ; ; (, Immuno-Oncology and Technology)
    Background: Glioblastoma (GBM) is an aggressive brain tumor giving a poor prognosis with the current treatment options. The advent of chimeric antigen receptor (CAR) T-cell therapy revolutionized the field of immunotherapy and has provided a new set of therapeutic options for refractory blood cancers. In an effort to apply this therapeutic approach to solid tumors, various immune cell types and CAR constructs are being studied. Notably, macrophages have recently emerged as potential candidates for targeting solid tumors, attributed to their inherent tumorinfiltrating capacity and abundant presence in the tumor microenvironment. Materials and methods: In this study, we developed a chemically defined differentiation protocol to generate macrophages from human pluripotent stem cells (hPSCs). A GBM-specific CAR was genetically incorporated into hPSCs to generate CAR hPSC-derived macrophages. Results: The CAR hPSC-derived macrophages exhibited potent anticancer activity against GBM cells in vitro. Conclusion: Our findings demonstrate the feasibility of generating functional CAR-macrophages from hPSCs for adoptive immunotherapy, thereby opening new avenues for the treatment of solid tumors, particularly GBM. 
    more » « less
  4. ; ; ; ; ; ; ; ; ; ; et al (, Cancers)
    Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors. 
    more » « less
  5. ; ; ; ; ; (, Journal of Immunology and Regenerative Medicine)
    Immunotherapy is a powerful technique where immune cells are modified to improve cytotoxicity against cancerous cells to treat cancers that do not respond to surgery, chemotherapy, or radiotherapy. Expressing chimeric antigen receptor (CAR) in immune cells, typically T lymphocytes, is a practical modification that drives an immune response against cancerous tissue. CAR-T efficacy is suboptimal in solid tumors due to the tumor microenvironment (TME) that limits T lymphocyte cytotoxicity. In this study, we demonstrate that neutrophils differentiated from human pluripotent stem cells modified with AAVS1-inserted CAR constructs showed a robust cytotoxic effect against prostate-specific membrane antigen (PSMA) expressing LNCaP cells as a model for prostate cancer in vitro. Our results suggest that engineered CAR can significantly enhance the neutrophil anti-tumor effect, providing a new avenue in treating prostate cancers. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email