Congratulations to Sydney Henriques a member of the Giorgio lab! Sydney鈥檚 paper 鈥淟ocally Reprogramming Tumor鈥慉ssociated Macrophages with Cytokine鈥慙oaded Injectable Cryogels for Breast Cancer鈥� has been selected as a VINSE spotlight publication.
Breast cancer remains the most prevalent cancer in the United States, causing more than 40,000 deaths annually. Within solid breast tumors, macrophages are the most abundant immune cell population and commonly adopt pro-tumor, immunosuppressive phenotypes that support cancer progression. Pro-inflammatory cytokines can reprogram these tumor-associated macrophages toward an anti-tumor state; however, systemic administration of cytokines at therapeutic doses produces severe toxicity, limiting clinical translation.
In this study, we developed a tough, injectable cryogel (an engineered hydrogel polymerized at 鈭�20 掳C) to enable localized delivery of immunomodulatory cytokines directly to the tumor microenvironment. This biomaterial depot provides sustained release around the tumor environment, while minimizing systemic exposure. We demonstrate that cytokine-loaded cryogels significantly repolarize tumor-associated macrophages toward an inflammatory, anti-tumor phenotype and reduce tumor progression in vivo.
Notably, at higher dosing levels, localized cytokine delivery via multiple cryogels also modulated immune populations in the lungs, a primary site of breast cancer metastasis, promoting pro-inflammatory immune activity associated with metastatic suppression. Together, these findings show that a locally delivered macrophage-reprogramming depot can remodel the immunosuppressive tumor microenvironment while supporting systemic anti-tumor immunity.
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Authors: Sydney R. Henriques, Evan B. Glass, Kristen L. Hoek, Ori Z. Chalom, Abigail E. Manning, Sohini Roy, Diana K. Graves, Sarah M. Goldstein, Benjamin C. Hacker, Renjie Jin, Marjan Rafat, Paula J. Hurley, Laura C. Kennedy, Young J. Kim, Andrew J. Wilson, Fiona E. Yul, Todd D. Giorgio
Purpose. Tumor-associated macrophages (TAMs) are the most abundant immune cells in primary solid tumors, including breast cancer, and typically exhibit an M2-like, immunosuppressive phenotype that promotes tumor growth. Given that TAMs can be repolarized through cytokine signaling, we propose a localized cytokine delivery depot using an injectable alginate cryogel to reprogram TAMs and create an inflammatory, anti-tumor TME.
Methods. The cryogels were fabricated using cryogelation to generate a macroporous structure, followed by ionic crosslinking to enhance mechanical integrity while preserving pore size distribution. In vitro studies were conducted using bone marrowderived macrophages, tumor-associated macrophages, and tumor explants. In vivo studies were conducted by orthotopically implanting breast tumors in the fat pads of FVB mice. Cell makeup and tissue composition were analyzed using qRT-PCR, flow cytometry, and Luminex panels. Statistical significance was determined using ANOVA and t-tests.
Results. In vitro, cryogels released chemokines and cytokines, attracted M2 macrophages, and repolarized them toward M1-like activities. In vivo, cryogel treatment increased the presence of M1 macrophages relative to M2 macrophages in both the primary tumor and lungs, reduced primary tumor growth, and decreased T-cell exhaustion.
Conclusions. A localized, injectable cryogel depot successfully induces an inflammatory TME, leading to reduced tumor burden and T-cell exhaustion while avoiding systemic toxicities associated with cytokine delivery.