Tumor Immunology

Reprogramming Tumor-associated Macrophages and Natural Killer Cells

While immunotherapy has become an effective means to attack drug-resistant cancer, breast cancer is deemed refractory to immunotherapy.  This is largely due to the immuno-suppressive breast cancer microenvironment predominated by M2-type tumor-associated macrophages (TAMs)1.  M2-type TAMs promote immuno-suppression and tumor cell growth through production of anti-inflammatory agents including polyamines, small polycationic metabolites involved in tissue damage repair and immuno-suppression2-5.  Numerous efforts have been made to convert immuno-suppressive M2-type to immuno-stimulatory M1-type TAMs, aiming to improve the immunogenicity of the tumor microenvironment.  While most of such studies utilize pro-inflammatory agent (e.g., LPS, IFN-γ, or TNFα) to promote M1 polarization of macropahges6,7,  such agents would potentially induce adverse systemic toxicity8.  Dr. Saori Furuta’s laboratory is thus investigating whether redirecting arginine metabolism from polyamine synthesis to nitric oxide (NO) synthesis could induce the immunogenic shift of TAMs. This approach is based on the fact that M1-type vs. M2-type TAMs are characterized by their differential usage of arginine. M1-type TAMs utilize arginine to synthesize NO for their immuno-stimulatory functions, whereas M2-type TAMs utilize arginine to synthesize polyamines for their immuno-suppressive functions. To this end, we employ dietary interventions or supplements to augment NO synthesis pathway, while suppressing polyamine synthesis pathway.  We found that tumor-associated natural killer (NK) cells also exist in the immuno-stimulatory NK1-type vs. immuno-suppressive NK2-type which are also characterized by their differential arginine usage. We are then testing the therapeutic efficacy of reprogramming NK2 to NK1 through the immunogenic shift of arginine metabolism. In ongoing studies, Dr. Bingcheng Wang’s laboratory has found that Eph receptor tyrosine kinases and their ephrin ligands regulate immune evasion in multiple cancer types including breast cancer, melanoma, prostate cancer, colorectal cancer, and lung cancer. Aberrant chemokine production and recruitment of MDSC (myeloid-derived suppressor cells) represent possible mechanisms underlying the effects. Deletion of EphA2 synergizes with immune checkpoint blockers to inhibit tumor development. They are developing new therapeutic agents based on their discoveries.

REFERENCES

1          Cassetta, L. & Kitamura, T. Macrophage targeting: opening new possibilities for cancer immunotherapy. Immunology, [Epub ahead of print] (2018).

2          Daghigh, F., Fukuto, J. M. & Ash, D. E. Inhibition of rat liver arginase by an intermediate in NO biosynthesis, NG-hydroxy-L-arginine: implications for the regulation of nitric oxide biosynthesis by arginase. Biochem Biophys Res Commun. 202, 174-180 (1994).

3          Hecker, M., Nematollahi, H., Hey, C., Busse, R. & Racké, K. Inhibition of arginase by NG-hydroxy-L-arginine in alveolar macrophages: implications for the utilization of L-arginine for nitric oxide synthesis. FEBS Lett 359, 251-254 (1995).

4          Bauer, P. M., Buga, G. M., Fukuto, J. M., Pegg, A. E. & Ignarro, L. J. Nitric oxide inhibits ornithine decarboxylase via S-nitrosylation of cysteine 360 in the active site of the enzyme. J Biol. Chem. 276, 34458-34464 (2001).

5          Tenu, J. P. et al. Effects of the new arginase inhibitor N(omega)-hydroxy-nor-L-arginine on NO synthase activity in murine macrophages. Nitric Oxide 3, 427-438 (1999).

6          Duluc, D. et al. Interferon-γ reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages. International Journal of Cancer 125, 367-373, doi:doi:10.1002/ijc.24401 (2009).

7          Kalish, S. V. et al. Macrophages Reprogrammed In Vitro Towards the M1 Phenotype and Activated with LPS Extend Lifespan of Mice with Ehrlich Ascites Carcinoma. Med Sci Monit Basic Res 21, 226-234 (2015).

8          Faulkner, L., Cooper, A., Fantino, C., Altmann, D. M. & Sriskandan, S. The mechanism of superantigen-mediated toxic shock: not a simple Th1 cytokine storm. J. Immunol. 175, 6870-6877 (2005).