Posted April 10, 2019
Lalita A. Shevde, Ph.D., University of Alabama at Birmingham

The immune system, normally responsible for finding and destroying cancer cells throughout the body, is often dysregulated in cancer, allowing tumor cells to evade detection and destruction. Macrophages, a type of immune cell, are found in high numbers surrounding tumors, with tumor-associated macrophages (TAMs) comprising anywhere from 5% to 50% of the tumor mass. High numbers of TAMs have been shown to correlate with poor prognosis and therapeutic resistance in patients. TAMs have also been shown to be highly flexible, with the capability of polarizing into either M2 (tumor-promoting) or M1 (tumor-killing) macrophages, depending on the signals produced by tumor cells. M2 macrophages have been shown to be strongly associated with tumors that grow quickly, are poorly differentiated, and are often estrogen receptor negative. The tumor-associated signals that regulate polarization of macrophages into the tumor-promoting M2 type rather than the tumor-killing M1 type are poorly understood. With a Fiscal Year 2013 (FY13) Breast Cancer Research Program (BCRP) Breakthrough Funding Level 1 Award, Dr. Lalita Shevde aimed to investigate how tumor-derived Hedgehog (Hh) signaling favors the polarization toward tumor promoting M2 macrophages and whether this signaling program can be reversed in order to promote M1 macrophages instead.

The Hh signaling pathway has been shown to be abnormally activated in numerous cancer types, including breast cancer. The activation of this pathway influences the environment surrounding tumors promoting tumor progression and metastasis. Despite extensive study of this pathway, its role in influencing tumor-associated immune cells, such as TAMs, remains largely unknown. As reported in a recent publication in Oncoimmunology, Dr. Shevde used in vitro models of breast cancer to demonstrate that tumor-derived Hh signaling factors activate M2 polarization through an upregulation of Hh signaling within the macrophages themselves. This signaling in turn activates a feedforward loop promoting further M2 polarization, which could potentially be prevented and/or reversed using genetic and pharmacological inhibitors of Hh signaling. 

Using an immunocompetent breast cancer mouse model, the team also demonstrated that mice treated with Vismodegib, an Hh inhibitor already approved by the U.S. Food and Drug Administration, had slower growing primary tumors that displayed more markers of apoptosis (tumor cell death) compared to control treated animals. Analysis of the tumors showed that Vismodegib changed the portfolio of immune cells surrounding the tumor. Vismodegib-treated mice had tumors with a significant reduction in the number of M2 macrophages with a concomitant increase in the number of tumor-killing M1 macrophages. Moreover, there was a significant decrease in the number of tumor-promoting myeloid-derived suppressor cells and T regulatory cells and an increase in tumor-killing dendritic cells, cytotoxic T cells, and activated helper T cells. More importantly, Vismodegib-treated mice exhibited a significantly fewer number of lung metastases compared to control-treated animals.

To examine the clinical significance of M2 macrophages in breast cancer, the team analyzed data from The Cancer Genome Atlas looking for markers of M2 polarization. Analyses revealed that M2 polarization markers were significantly upregulated across all breast cancer subtypes, with the M1 macrophage marker CD40 being significantly reduced in HER2-enriched and luminal breast cancer subtypes.

Dr. Shevde received follow-on funding through the Department of Defense’s (DoD’s) BCRP with a Breakthrough Funding Level 2 Award to continue her work testing whether inhibition of the Hh pathway will rewire macrophages leading to anti-tumor immunity. Dr. Shevde stated, “We established a new concept that breast cancer cells mediate a ‘conversation’ or a crosstalk with tumor-infiltrating macrophages via Hedgehog ligands that act as ‘conversational’ molecules; this results in immense molecular changes in macrophages that functionally recalibrates them to an immune-suppressive, tumor-promoting state. I am very grateful to the DoD BCRP for funding my research program over the past several years on Hedgehog signaling; cumulatively, these investments have enabled me to take on new challenges to modify the breast tumor microenvironment towards eliminating breast cancer.”

This work, pioneered by Dr. Shevde, has led to the discovery of this novel signaling paradigm. Many of the macrophage-targeting treatments currently in clinical trials abrogate not just the recruitment of M2 macrophages but M1 as well. Thus, more targeted approaches, such as the one Dr. Shevde is taking, are needed so as to specifically target the tumor-promoting macrophages while preserving the function and integrity of the tumor-killing M1 macrophages.

Lab team photo: Dr. Shevde (first person on the right)

 

Publication:

Hanna A, Metge BJ, Bailey SK, et al. 2018. Inhibition of hedgehog signaling reprograms the dysfunctional immune microenvironment in breast cancer. Oncoimmunology 8(3): Epub ahead of print https://doi.org/10.1080/2162402X.2018.1548241.

Links:

Public and Technical Abstracts: Breast Tumor Tissue-Derived Hedgehog Morphogens Immunoedit the Polarization of Breast Cancer-Associated Macrophages

Public and Technical Abstracts: Sculpting Antitumor Immunity as an Approach to Treat Metastatic Breast Cancer

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