In the recent years there has been a significant advance in our understanding of neutrophil function in cancer initiation, progression and metastatic spread. We now know that neutrophils may play various, sometime conflicting roles in cancer and may either act to promote or limit tumor growth and metastatic progression. Since neutrophils were traditionally considered to be a homogeneous population of terminally differentiated cells, the conflicting reports regarding neutrophils in cancer fueled a heated controversy. The study of neutrophil function in cancer, performed in our lab, indicated that rather than being a homogeneous population, circulating neutrophils may be divided to 3 different subpopulations that differ physically, morphologically and most importantly, differ functionally. We then identified these subsets in other inflammatory scenarios suggesting that the appearance of various neutrophil subsets is a more common phenomenon. With this understanding, we are looking to characterize various aspects of neutrophil function in cancer and in other diseases. Also, we believe that our understanding of neutrophil subset versatility is just the tip of the iceberg and we are actively looking to characterize new neutrophil subsets.
Neutrophil subset heterogeneity
Neutrophils were traditionally considered to be a homogeneous population of terminally differentiated cells with limited plasticity. This view is rapidly changing and several studies, including our own, have demonstrated the existence of various neutrophil subsets with distinct functions. In cancer, we identified at least 3 different neutrophil subsets: Normal Density Neutrophils (NDN), mature Low Density Neutrophils (LDN) and immature Low Density Neutrophils (LDN). These neutrophil subsets harbor either pro- (mature and immature LDN) or anti-tumor properties and our hypothesis is that the overall contribution of neutrophils to cancer progression is dictated by the ratio between these subsets. Distinct neutrophil subsets exist not only in the context of cancer but also in other clinical conditions. We are currently exploring neutrophil diversity, at the single neutrophil level, in various clinical conditions looking to identify and characterize novel neutrophil subsets.
The molecular mechanisms regulating neutrophil cytotoxicity in cancer
Neutrophils play a critical role in cancer and both tumor-promoting and anti-tumor neutrophil subpopulations have been described. The anti-tumor neutrophil subpopulation has the capacity to kill tumor cell and limit metastatic spread. However, we noticed that not all tumor cells are equally susceptible to neutrophil cytotoxicity. Since those cells that evade neutrophils have greater chances of forming metastases we explored the mechanism neutrophils employ to kill tumor cells. We have previously shown that neutrophils cytotoxicity is mediated by secretion of H2O2. Our new data show that H2O2 dependent neutrophil cytotoxicity is Ca2+ dependent and is mediated by TRPM2, a ubiquitously expressed H2O2-dependent Ca2+ channel. Tumor cells express higher levels of TRPM2 than their neighboring non-malignant cells, rendering tumor cells more susceptible to neutrophil cytotoxicity. However, circulating tumor cells, expressing reduced levels of TRPM2, are not susceptible to neutrophil cytotoxicity and are more efficient metastatic seeders.
The molecular basis for neutrophil recognition of tumor cells
On top of playing a key role in host defense against invading pathogens and in mounting the immune response, neutrophils can also kill tumor cells. Neutrophils are equipped with a variety of receptor that identify microbes, however, the mechansim of tumor cell recognition remains a major question for understanding the role neutrophils play in cancer. To answer this question we are using various approaches including neutralizing antibodies, soluble receptors that act as decoy molecules and neutrophils isolated from receptor knockout mice. This strategy aims at identifying both the neutrophil expressed receptor and the tumor cell ligands. Insight into the mechanism of tumor cell recognition will shed light on a critical aspect of neutrophil function in cancer and may also provide a better understanding of why/how certain tumor cells evade neutrophils.
Underlying Hyperglycemia in Cancer and the consequences for neutrophil function
Diabetes patients are at an increased risk of being diagnosed with cancer and face poorer prognosis mainly due to increased metastatic spread. With diabetes rates continuously rising, understanding why cancer patients with underlying diabetes are more susceptible to develop metastatic disease is of upmost importance. In previous studies, we have shown that neutrophils have the capacity to limit metastatic seeding. This knowledge, together with reports suggesting that neutrophil function is impaired in hyperglycemia, prompted us to test whether increased metastatic spread in diabetes is a result of hyperglycemia-induced neutrophil dysfunction. Our data show that while primary tumor growth is attenuated in hyperglycemia, metastatic progression is enhanced. Surprisingly, although neutrophil mobilization is impaired in hyperglycemic tumor bearing mice, neutrophil function remains intact. We find that reduced neutrophil mobilization in hyperglycemic mice during the premetastatic stage results in an increase in metastatic seeding. Finally, our data show that while normalizing glucose levels rescues primary tumor growth, it concomitantly restores neutrophil mobilization and reduces metastatic seeding in the lungs. Taken together, our results show that impaired neutrophil mobilization in hyperglycemic tumor bearing mice leads to an increase in metastatic seeding and therefore to a worse outcome.
Neutrophils' Function in Malaria
Malaria, is one of the major infectious diseases influencing human kind today. Plasmodium falciparum is the protozoan parasite responsible for the deadliest form of human malaria. This parasite is estimated to infect hundreds million people worldwide each year, resulting in approximately half a million deaths, primarily of young children. Over the past decades significant efforts were invested in trying to understand immune responses to malaria infections. In this regard, there have been major advances in our understanding of adaptive immune responses to malaria whereas the role of innate immunity received much less attention. We are interested in further investigating the roles neutrophils play in the innate response to malaria infections.