Newly identified subpopulation of NK cells with the promise to treat obesity-associated pathologies: diabetes and cancer

Immune cells reside in organs under physiological conditions and serve as important regulators of tissue homeostasis and metabolism in lean individuals. On the other hand, coupled to overnutrition and a sedentary lifestyle, these give rise to chronic, low-grade tissue inflammation (called “metaflammation”), which contributes to the development of obesity and associated diseases as type 2 diabetes and several cancer indications.

The cellular network of metaflammation is complex and not completely understood. Although studies in obese mouse models have recently revealed the general importance of NK cells for metaflammation, the details remained unclear.

Our scientists have identified a unique, previously uncharacterized subpopulation of NK cells, termed “myNK cells”, showing a distinct expression pattern of myeloid cell associated genes (such as IL6R, CSF1R and others) in obese mice and humans. In mice, the selective ablation of myNK cells significantly decreases weight gain, the degree of metaflammation and insulin resistance despite high fat diet feeding (Fig. 1). In humans, myNK cells numbers in the peripheral blood correlated with the degree of metaflammation and decreased upon significant weight loss.

The formation and recruitment of myNK cells could be shown to critically depend on IL6/Stat3 signaling, as blocking this pathway abrogated myNK cell formation and recapitulated the beneficial phenotype, i.e. improved glucose metabolism and decreased weight gain and metaflammation under high fat diet feeding.

Obesity and metaflammation are significant risk factors for a variety of cancer entities including solid tumors such as gastrointestinal cancers, gynecological cancers, and multiple myeloma as a hematologic malignancy. In the light of this, tumor samples of obese patients were analyzed for the existence of myNK cells by co-stainings for CD56 (NK cell marker) plus IL6Ra. Indeed, myNK cells could be detected in tumor tissues of a number of selected cancer entities such esophageal (Fig. 2), pancreatic and colon carcinoma, endometrium and breast cancer, as well as multiple myeloma.

As a number of genes that are uniquely upregulated in this NK cell subpopulation have been identified, selective targeting of an upregulated marker in myNK cells or a specific combination of an NK cell marker plus one of the upregulated myeloid markers might open the door for immunotherapy as a treatment option of obesity, diabetes and certain obesity-associated cancer entities.

Fig. 1: Depletion of the myeloid NK cells reduces obesity and improves metabolism in HFD fed mice

Fig. 2: Myeloid NK cells can be detected in tumor tissue of esophagus carcinoma

We are now looking for either a licensing partner, or a collaboration partner to further develop this project.

PCT application was filed on 24.04.2018 (EP18/060509).

DOI: 10.1016/j.cmet.2017.05.018