Cancer Prevention Drug?

I recently found a fascinating news release on the Loyola Chicago SOM website related to immunology and cancer. The results of the study has significant implications for our understanding of cancer treatment. Basically, researchers at the university discovered that a molecule named TGF-b, already known for its anti-proliferative effects on early cancer cells, could in fact amplify our immune response. Given that "evading the immune system" was an emerging hallmark of cancer in Hanahan and Weinberg's article, I thought that this was an appropriate article to choose. 


We know that our immune system regularly find and destroys abnormally functioning cells. However, every now and then cancer cells are somehow able to avoid detection. Using TGF-b, could we enhance our immune system as part of a preventative drug treatment against cancer? 

Overview:

The mechanism that the authors studied involves the balance between effector T-cells and regulatory T-cells. This proposed mechanism suggests that our immune system's ability to attack cancer cells  is dependent on a balance between the number of effector T-cells and regulatory T-cells. Heres how it works normally:


1) Effector T-cells target tumor cells or those infected by pathogens. However, if you have too many then you can develop an autoimmune disorder. That is why...


2) Effector T-cells are regulated by regulatory T-cells. Regulatory T-cells ensure that effector T-cells do not destroy healthy tissue. However, if regulation is too tight, effector T-cells may not be able to destroy tumors. 


Heres were TGF-b comes into play. For some time, TGF-b has been known to control cell proliferation and cellular differentiation. However, Loyola researchers found a novel for for TGF-b. It turns out that the molecule is responsible for regulating apoptosis in regulatory and effector T-cells.  I will now to describe the research article and how researchers discovered TGF-b's role in the homeostasis of both regulatory and effector T-cells. 

Results:

Researchers had observed that under certain conditions*, effector T-cells would undergo p53-induced CD28-dependent apoptosis (PICA) while regulatory T-cells would not. This suggested that the mechanism for the survival of each cells was different. The researchers hypothesized that the key difference was TGF-b! Below are the experiments they did and their results (all experiment were conducted on mice):

1) The authors cultured effector T-cells in apoptotic conditions in the presence or absence of TGF-b
Result: Exogenous TGF-b makes effector T-cells resistant to apoptotic conditions*. 

Effector T-cell growth in the presence and absence of TGF-b

2)The authors inhibited the TGF-b receptor on regulatory T-cells and cultured them in apoptotic conditions in the presence or absence of TGF-b. 
Result: 1) TGF-b signaling is necessary for regulatory T-cell survival from apoptotic conditions*. (TFG-signaling in regulatory T-cells are autocrine)


3) The authors measured levels on IL-9 in PICA rescued effector T-cells (cytokine produced by a specific type of T-cell).
Result: Exogenous TGF-b causes effector T-cells to differentiate into Th9 cells under apoptotic conditions*.


*a combination of immobilized anti-CD3 and anti-CD28 Abs


To summarize, the researchers discovered a novel role for TGF-b, a molecule previously thought to be an immunorepressor. They found that in apoptotic conditions, TGF-b can confer resistance to apoptosis in effector T-cells. Additionally, TGF-b induces differentiation into Th9 cells. 

Implications/Questions:

So what exactly are the implications of these findings in the field of cancer? Neither the news release or the primary article elaborated much on the this subject so here is my attempt at a conclusion.  

There seem to be several things going on at the same time. Based on Hanahan and Weinberg reading we know that TGF-b  has anti-proliferation effects on early cancer cells but encourages malignancy in late-stage tumors (649). We further know that TGF-b can actually be secreted by cancer cells as a way of paralyzing Natural Killer (NK) and Cytotoxic T-cells (CTL) cells (661).  Based on the Loyola article, we know that TGF-b can save T-cells from apoptotic conditions. 

Thus, it appears as though the role of TGF-b changes depending on the cell or tumor environment. Ideally, we would want to use TGF-b to our advantage; in an environment where it will 1) have anti-proliferation effects on cancer cells 2) augment effector T-cells and 3) not paralyze NK and CTL cells. 


More research will need to be done to create an effective drug. Below are some of my thoughts:


1) Using TGF-b, how do we maximize effector T-cell activity against cancer cells without stimulating an unwanted autoimmune response?


2) TGF-b seems to have opposite effects on effector/regulatory T-cells and NK/CTL. What environment will enable us to optimize levels of these cells?


3) Could TGF-b be used as preventative treatment against cancer?


4) What are the various changes that TGF-b makes to the immune system as well as cancer cells at various stages of tumor development?


Please feel free to comment if you have any thought or questions!