CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T Cell Checkpoint Immunotherapy in Pancreatic Cancer Models

By Yu Zhu, B. Knolhoff, M. Meyer, T. Nywening, B. West, Jingqin R Luo, A. Wang-Gillam, S. Goedegebuure, D. Linehan, D. DeNardo. Cancer Research, 2014

1,178 citations recorded by the source corpus.

Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment. Critical drivers of immune escape in the tumor microenvironment include tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC), which not only mediate immune suppression but also promote metastatic dissemination and impart resistance to cytotoxic therapies. Thus, strategies to ablate the effects of these myeloid cell populations may offer great therapeutic potential. In this report, we demonstrate in a mouse model of pancreatic ductal adenocarcinoma (PDAC) that inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive anti-tumor T cell responses. Investigations of this response revealed that CSF1R blockade also upregulated T cell checkpoint molecules, including PDL1 and CTLA4, thereby restraining beneficial therapeutic effects. We found that PD1 and CTLA4 antagonists showed limited efficacy as single agents to restrain PDAC growth, but that that combining these agents with CSF1R blockade potently elicited tumor regressions, even in larger established tumors. Taken together, our findings provide a rationale to reprogram immunosuppressive myeloid cell populations in the tumor microenvironment under conditions that can significantly empower the therapeutic effects of checkpoint-based immunotherapeutics.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/02f0a892ebb082fb4104c754ea87551cb2c0160c

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Citations in the corpus

Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kγ to Promote Pancreatic Cancer Metastasis. (2018, background): “(35) Macrophages, especially M2 macrophages, play dramatically significant roles in tumor initiation and progression, as they can stimulate immune-suppression, metastasis, and resistance to anti-cancer therapy (20,36,37).”
Ferroptosis in cancer therapy: a novel approach to reversing drug resistance (2022, background): “demonstrated that reprogramming TAMs by blocking CSF1/CSF1R enhanced the efficacy of immune checkpoint inhibitors in pancreatic cancer [62].”
Oral squamous cell carcinomas: state of the field and emerging directions (2023, background): “A higher ratio of M2 to M1 TAMs is commonly observed in the peritumoral microenvironment surrounding OSCC, promoting carcinogenesis.(309,310) MDSCs are immature myeloid-derived cells which can suppress T cells.”