Chemerin as an Immunotherapeutic Agent in Breast Cancer

Institution: Palo Alto Veterans Institute for Research
Investigator(s): Russell Pachynski, M.D. -
Award Cycle: 2009 (Cycle 15) Grant #: 15FB-0117 Award: $89,600
Award Type: Postdoctoral Fellowship
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2009)

Cancer immunotherapy offers the potential of potent anti-tumor responses while avoiding non-specific toxicities associated with traditional cytotoxic chemotherapy. Localization of key immune cells to tumor sites has been shown to be important for anti-tumor efficacy in multiple animal tumor models and in clinical studies. Studies have shown the importance of the localization of key immune cells, such as NK (natural killer) and dendritic cells in the immune response to breast cancer. Chemerin is a recently described chemoattractant initially isolated from human inflammatory fluids (malignant ascites and rheumatoid synovial fluid). Chemokine-like receptor 1 (CMKLR1) constitutes the main cellular receptor for chemerin, and is expressed by macrophages, natural killer (NK) cells, and immature dendritic cells (DCs). Our lab has worked to characterize chemerin and its receptor CMKLR1, and has made CMKLR1 “knockout” mice that lack the receptor to study the underlying biology. Additionally, we have made several antibodies against the receptor that can act to block its function. This background provides us particularly powerful tools to investigate the specific cellular and molecular mechanisms that mediate the anti-tumor effects of chemerin.

Our studies are aimed at evaluating chemerin as a novel immunotherapeutic agent in a mouse model of breast cancer. The project aims include:
1) Testing whether increased concentrations of chemerin at sites of tumor will result in decreased tumor growth;
2) Chemerin’s effect on the representation of macrophages, NK, and dendritic cells in chemerin-expressing tumors, and whether chemerin may further act to alter the functionality of these recruited cells resulting in anti-tumor effects; and
3) Determining whether the tumor-modifying effects of chemerin are mediated by chemokine-like, CMKLR1 receptor.

For these studies, we have produced breast and other tumor lines that express chemerin in an inducible manner. This gives us the tools to study the recruitment of immune cells to these tumors and the relative importance of chemerin and the CMKLR1 receptor. We will use flow cytometry and immunohistochemistry techniques to evaluate the results of these experiments.

We hope the results from these studies will indicate the most promising clinical uses for chemerin. For example, chemerin could be injected locally into breast tumors or administered systemically in its inactive form, as it can be activated by tumor-derived factors. Given its function as a leukocyte chemoattractant, it might also be used as an adjuvant with or without cytotoxic chemotherapies. Additionally, it could be combined with other antibody-based therapies, such as Herceptin to help augment antibody dependent cell-mediated cytotoxicity (ADCC) and efficacy of the immune response.




Final Report (2011)

Cancer immunotherapy aims to use the immune system to fight cancer. This type of approach has the potential to be extremely potent and specific without the toxicities and side effects normally seen with traditional treatments like chemotherapy and radiation. Breast cancer is the most common cancer in women, and more effective treatments are needed. Chemerin is a novel protein normally found in the body. It acts to attract and recruit immune cells towards areas of high concentration of chemerin. Our project involves evaluating this newly discovered protein as a type of immunotherapy in breast cancer. The goal is to use chemerin to attract anti-tumor immune cells to the tumor in order to reduce or eliminate tumor growth.

Our research thus far has been able to accomplish many of the proposed aims. We have been able to show that injecting or overexpressing chemerin in breast tumors in a mouse model is able to reduce or eliminate tumor growth. We have shown that tumors treated with chemerin show increased numbers or frequency of immune cells compared to controls. We have shown that there is a reduced incidence of tumor formation after treatment with chemerin. We have shown that the anti-tumor effect of chemerin is eliminated in mice that do not have the receptor for chemerin in a melanoma model. However, we were unable to show this in our breast cancer model, likely due to strain-specific differences and the presence of other receptors for chemerin. We plan to continue investigating the exact mechanisms of chemerin's anti-tumor effect using a variety of techniques.



The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses
Periodical:Journal of Experiemental Medicine
Index Medicus:
Authors: Pachynski RK, Zabel BA, Kohrt HE, Tejeda NM, Monnier J, Swanson CD, Holzer AK, Gentles AJ,
Yr: 2012 Vol: 209 Nbr: 8 Abs: Pg:1427-1435