Friday, May 4, 2012

Immunological Turncoats Ward off Tumour Eradication

Confocal microscope image of a spontaneous breast cancer tumor in a mouse. (Credit: Image courtesy of University of California - San Francisco)

This news report from ScienceDaily highlights how much progress has been made in our understanding of cancer. The picture is beautiful because it presents an image of what has long been suspected. 

As the news article states ....

Instead, these immune cells are headed off at the pass. A completely separate set of healthy cells that are already in contact with the tumor effectively establish a defensive perimeter around it.
This is very important information, it provides insight into one of the fundamental mysteries of cancer: why the immune system can both recognise and mount a T cell attack that gets headed off at the pass. Cancer Immunotherapy began long ago with a chap named Steven Rosenberg ...
 In 1997 I read The Transformed Cell: Unlocking the Mysteries of Cancer. At that time I was taking many notes on the books I was reading but for this book I wrote:
Story very exasperating for first 15 years. This man worked incredibly hard and persevered for very meagre results for this time but book very well written though needs better terminology explanation (has glossary). Finally began achieving success with interleukin 2 (il2) ...
Exasperating is an understatement. Even today cancer remains baffling in its diversity and genomics. What I do remember about this book is the constant frustration the authors expressed at being able to culture T cells that would respond to tumour cells in vivo, but when injected into the patient simply disappeared. They received the worst case patients, often conducted operations that involved removing shoulders and hips to reduce tumour mass, but their patients just kept dying. The pioneering work in any scientific endeavour is often a cacophony of mis-understanding and lack of sufficient information. The pioneers pave the road so the going is much smoother for others. Today we are witnessing the fruits of the pioneers in cancer immunotherapy.

When Rosenberg first conducted his experiments he had no hope of understanding why those activated T cells vanished. We simply didn't know enough, we didn't know about these cells that ward off an immune attack against tumours. It is only in recent years we have come to realise that these cells, sometimes referred to as Treg cells, play a fundamental role in modulating inflammation and immunity. They are only a small subset of the total T cell population but have enormous influence over T cell function. Cancerous cells, or at least a very small percentage of them, have happenchanced upon a release of mediators that attracts these Treg cells and so prevent an immunological assault. A recent study on melanoma highlights this.

For the intense medico version of how Tregs via CTLA-4 might be inhibiting cancer suppression go to this link. Very good article at Medscape but not for the faint hearted. Additionally, you may need to be registered(free) to read the article. For a "I know I'm not going to understanding all of this but will give it a shot anyway"(which is what you should always do with difficult material!), this recent research article on CTLA-4 and melanoma is worth reading.

Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma.

Article can be downloaded at the relevant link. 

The John version goes likes this:

  1. CTLA-4 is a molecule that binds to receptors on T cells and inhibits their function.
  2. In particular but not solely, CTLA-4 is found in T reg and myeloid derived suppression cells
  3. The above cells are known to gather around tumours, this is believed to be caused by expression of  chemokines, the relevant chemokine can vary across tumour types. These chemokines can attract T regs(see abstract below marked *). There are other agents which will attract Tregs and MDSCs, which creates another set of problems.
  4. Although T cells will be attracted to a tumour with high numbers of Tregs and MDSCs present these cells will not attact the tumour. As noted in the Medscape article:
Regulatory T cells and myeloid-derived suppression cells seem to play an important role in inducing tolerance and in the downregulation of immune responses to tumor antigen through the production of immune suppressive IL-10 and transforming growth factor beta (TGF-beta) and by increasing their expression of inhibitory molecules such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)
Note the reference to il10 and TGF-beta, this is very important and creates a quandary for while vitamin D is clearly important for cancer prevention, given its capacity to increase both of these cytokines I have to wonder about the wisdom of high vitamin D with an established tumour. I sometimes think that if a person has a cancer they should alternate between inducing inflammation and then reducing it in the hope that the increased inflammatory state will overwhelm the inhibitory effects of il10 and tgf beta.

As I read only a few days ago a key strategy in addressing cancer may well be the reduction in Treg numbers. Melatonin has long been associated with anti-tumour activity and this study is consistent with the above remarks about Tregs and MDSCs. Thankfully it is found that melatonin suppresses the generation of Tregs and  this was consistent with its anti-tumour activity ... 

1. In Vivo. 2010 Sep-Oct;24(5):787-9.

Psychoneuroendocrine modulation of regulatory T lymphocyte system: in vivo and in vitro effects of the pineal immunomodulating hormone melatonin.

Vigoré L, Messina G, Brivio F, Fumagalli L, Rovelli F, DI Fede G, Lissoni P.

Laboratory of Immunomicrobiology, S. Gerardo Hospital, Monza, Milan, Italy.

BACKGROUND: At present, it is known that cancer-related immunosuppression would mainly depend on an immunosuppressive action mediated by a subtype of CD4+ lymphocytes, the so-called regulatory T lymphocytes (T-reg), which are identified as CD4+CD25+ cells. Moreover, it has been shown that anticancer immunity is under psychoneuroendocrine regulation, mainly mediated by the pineal hormone melatonin (MLT). This study was performed to investigate the in vivo and in vitro effects of MLT on T-reg generation. MATERIALS AND METHODS: We evaluated the in vivo effects of MLT (20 mg/daily orally in the evening) in 20 patients with untreatable metastatic solid tumor and the in vitro effects of MLT incubation (at 10 and 100 pg/ml) of pure lymphocyte cultures on T-reg cell count. RESULTS: MLT induced a statistically significant decline in mean T-reg cell numbers in patients who achieved disease control, whereas no effect was seen in those who had progressed. In contrast, no in vitro effect of MLT incubation was apparent. CONCLUSION: This preliminary study would suggest that MLT may exert in vivo an inhibitory action on T-reg cell generation in cancer patients which is associated with a control of the neoplastic progression, whereas no direct effect was seen in vitro on lymphocyte differentiation. This finding would suggest that MLT may counteract T-reg cell generation in vivo by inhibiting macrophage activity which is involved in stimulating T-reg cell production.

PMID: 20952751  [PubMed - indexed for MEDLINE]

As you can now see I am getting lost in a tangle of associations here. I could keep going and going but there is no point, there is so much data it is far too easy to create convincing explanations as what cancer is and how it can be treated. There are too many proclaiming solutions because they do not see the complexity, they do not keep reading until they become confused or even worse stop reading when they become confused the cowards. 

*1. J Immunol. 2012 May 1;188(9):4209-16. Epub 2012 Mar 26.

Control of Transplant Tolerance and Intragraft Regulatory T Cell Localization by
Myeloid-Derived Suppressor Cells and CCL5.

Dilek N, Poirier N, Usal C, Martinet B, Blancho G, Vanhove B.

INSERM, Unité Mixte de Recherche en Santé 1064, Nantes F-44093, France;

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that are believed to inhibit immune responses in the contexts of cancer and organ transplantation, in association with regulatory T cells (Treg). However, the way in which MDSC cooperate with Treg remains elusive. In this study, we used DNA microarrays to analyze gene expression in blood-derived MDSC from rat recipients of kidney allografts. We found CCL5 (Rantes), a chemotactic C-C motif 5 chemokine, to be strongly downregulated after treatment with a tolerizing regimen. The amount of CCL5 protein was also lower in the plasma of tolerant recipients, whereas intragraft CCL5 was unchanged. Because CCL5 is chemotactic for Treg, we hypothesized that a gradient of CCL5 between the graft and peripheral blood might contribute to the intragraft localization of Treg in tolerant animals. To test this hypothesis, we treated tolerant rat recipients of kidney allografts with recombinant rat CCL5 to restore normal plasma concentrations. This led to a strong reduction in intragraft Treg monitored by immunohistofluorescence and by quantitative real-time PCR measurement of Foxp3 mRNA. Ultimately, this treatment led to an increase in serum creatinine concentrations and to kidney graft rejection after about a month. The kidney function of syngeneic grafts was not affected by a similar administration of CCL5. These data highlight the contribution of MDSC to the establishment of a graft-to-periphery CCL5 gradient in tolerant kidney allograft recipients, which controls recruitment of Treg to the graft where they likely contribute to maintaining tolerance.

PMID: 22450806  [PubMed - in process]

Note this study though, for glioma cells it is different chemokine(CCL2) that attract Tregs.


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