Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression and improves chemotherapeutic responses

By J. Mitchem, D. Brennan, B. Knolhoff, B. Belt, Yu Zhu, D. Sanford, Larisa Belaygorod, D. Carpenter, Lynne I Collins, D. Piwnica-Worms and 9 more. Cancer Research, 2012

902 citations recorded by the source corpus.

Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by inhibiting either the myeloid cell receptors CSF1R or CCR2 decreases the number of tumor-initiating cells in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis and increases anti-tumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8+ T lymphocytes. Together, our findings show how targeting tumor-infiltrating macrophages can effectively overcome therapeutic resistance mediated by tumor-initiating cells.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/bdba172e5e8cad21ea65cb0f0240fd2917e74ee0

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Guido Kroemer
2. L. Galluzzi
3. A. Mantovani
4. L. Zitvogel
5. Oliver Kepp
6. P. Allavena
7. A. Buqué
8. D. DeNardo

In Oncology

1. A. Mantovani
2. P. Allavena
3. Guido Kroemer
4. L. Galluzzi
5. L. Zitvogel
6. Zena Werb
7. J. Erler
8. Oliver Kepp

Citations in the corpus

• The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? (2015, positive): “Depletion of TAMs or IMs by inhibiting either CCR2 or M-CSF receptor resulted in decreased CSCs in pancreatic tumors, improved chemotherapeutic efficacy, inhibited metastasis, and increased antitumor T cell responses (Mitchem et al., 2013).”
• Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy (2015, positive): “Moreover, while specific immune cell infiltration has been suggestive of a poor prognosis (Mitchem et al , 2013), leukocyte infiltration per se can confer a good prognosis in PDAC and in other cancer types (Caruso et al , 2002; Jamieson et al , 2012).”
• The interaction of anticancer therapies with tumor-associated macrophages (2015, background): “In primary tumors and in metastatic sites, tumorassociated macrophages (TAMs) engage in complex bidirectional interactions with tumor cells, cancer stem cells (CSCs), fibroblasts, mesenchymal stem cells, endothelial cells, and T, B, and NK cells.”
• CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T Cell Checkpoint Immunotherapy in Pancreatic Cancer Models (2014, positive): “signaling could improve the efficacy of chemotherapy in murine PDAC models by enhancing chemotherapy-induced antitumor immunity (11).”
• Role of interleukin-6 in cancer progression and therapeutic resistance (2016, neutral): “macrophages, T cells and epithelial cells [43, 57, 58].”
• Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment (2018, background): “Moreover, TAM also directly induces CSC properties of pancreatic tumor cells by activating signal transducer and activator of transcription 3 (STAT3) and thus inhibits the antitumor CD8 T lymphocyte responses in the chemotherapeutic response [131].”
• Tumor-associated macrophages: from basic research to clinical application (2017, background): “As such, CSF1R blockade has been shown to increase the efficacy of chemotherapy for pancreatic tumors [83].”
• M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide (2015, background): “Many studies have shown on one hand an inverse correlation between macrophage abundance in a tumor and patient prognosis and survival, and on the other hand a positive correlation with resistance to chemotherapy [11, 27–29].”
• Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. (2015, background): “Immunological Effects of Targeted Anticancer Agents Agent Setting Effect Notes Reference Bevacizumab transplantable murine CRC depletes TREG cells mechanism involving KDR Terme et al., 2013 Dasatinib CML favors the expansion of circulating CTLs and NK cells correlates with molecular response to chem”