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Driving tumor-associated macrophages to a CXCL9Hi/SPP1Low phenotype eliminates pancreatic cancer
Yen T M Nguyen1, Marc Pfefferlé2, Juhyun Oh3
1Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with limited therapeutic options. Recent studies reveal the complex PDAC microenvironment, which fosters interactions between various cell types that contribute to immunosuppression. Among these, tumor-associated myeloid cells with a CXCL9-low, SPP1-high phenotype are particularly abundant and play a significant role in promoting disease progression. We hypothesize that targeting these cells can reprogram the tumor microenvironment and improve survival outcomes. To test this, we develop a myeloid cell-targeting nanoformulation, CANDI470, designed to increase CXCL9 expression and reduce SPP1 levels in tumor-associated myeloid cells. Our results demonstrate that this approach not only enhances immune responses but also achieves remarkable therapeutic efficacy, including cures in murine PDAC models, even when used as a monotherapy. This myeloid cell modulation strategy represents a promising therapeutic avenue for PDAC, offering hope for improved treatment for this otherwise difficult-to-treat malignancy.
Insights
Targeting specific myeloid cells in pancreatic cancer (PDAC) with a novel nanoformulation reprogrammed the tumor microenvironment. This approach enhanced immune responses and achieved cures in preclinical models, offering a new therapeutic strategy for PDAC.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options.
- The PDAC tumor microenvironment is immunosuppressive, driven by specific myeloid cell populations.
- Tumor-associated myeloid cells with a CXCL9-low, SPP1-high phenotype promote PDAC progression.
Purpose of the Study:
- To investigate the therapeutic potential of targeting tumor-associated myeloid cells in PDAC.
- To develop and evaluate a myeloid cell-targeting nanoformulation (CANDI470) to modulate the PDAC microenvironment.
- To assess the impact of myeloid cell modulation on immune responses and therapeutic efficacy in PDAC models.
Main Methods:
- Development of a novel nanoformulation, CANDI470, designed to target myeloid cells.
- Administration of CANDI470 to murine PDAC models.
- Analysis of changes in myeloid cell phenotype (CXCL9 and SPP1 levels) within the tumor microenvironment.
- Evaluation of immune responses and tumor progression following treatment.
Main Results:
- CANDI470 successfully targeted tumor-associated myeloid cells, increasing CXCL9 and decreasing SPP1 expression.
- Myeloid cell modulation led to enhanced anti-tumor immune responses.
- CANDI470 demonstrated significant therapeutic efficacy, achieving complete tumor regression and cures in murine PDAC models as monotherapy.
- The nanoformulation strategy effectively reprogrammed the immunosuppressive tumor microenvironment.
Conclusions:
- Targeting specific myeloid cell phenotypes in PDAC is a viable therapeutic strategy.
- The nanoformulation CANDI470 shows promise for reprogramming the PDAC tumor microenvironment and enhancing anti-tumor immunity.
- Myeloid cell modulation represents a novel and potentially curative approach for pancreatic ductal adenocarcinoma.
