Ultimate fate of cellular immune responses is determined by the balance between positive & negative signals delivered by T-cells..Melanoma ..Jim Breit

ICOS Expression,To secrete and what to secrete is the question.







My research has taken me to the costimulators and coinhibitors of the T-cell activation. The Delicate balance between the costimulators and coinhibitors render the right immune response at the right time. One of these costimulators is the ICOS. But if there is to much ICOS, then there is a down regulation of the the immune response by the secetion of IL-10 into the tumor's microenviroment.

The level of ICOS surface expression regulates the magnitude of the in vivo Th1/Th2 ratio, perhaps by influencing Th2 differentiation. This regulation plays a major role in the differentiation of the T-cells.


The linkage between low ICOS expression and “early” cytokines, and between intermediate/high ICOS expression and “late” cytokines is intriguing and could mean that ICOS is gradually up-regulated in the course of progressing T cell differentiation.

ICOS-low-cells were found to be loosely associated with the early cytokines interleukin (IL)-2, IL-3, IL-6, and interferon (IFN)-gamma.

ICOS-medium cells, the large majority of ICOS_ T cells in vivo, were very tightly associated with the synthesis of the T-helper type 2 (Th2) cytokines IL-4, IL-5, and IL-13, and these cells exhibited potent inflammatoryeffects in vivo.

In contrast, ICOS-highT cells were highly and selectively linked to the antiinflammatory cytokine IL-10.

The strength of the effector response of Th cells is regulated by the control of ICOS expression.

Overall, this data seem to indicate that ICOS cell surface density serves as a regulatory mechanism for the release of cytokines with different immunological properties.

We want the low expression of ICOS which seems to differeniate the niave T-cells towards the TH1 T-cell phenotype. We can accomplish that with Yervoy (Anti-CTLA-4). STAT5 signaling is found in both the Th2 and Treg pathway.It just so happens Yervoy causes the phosphorylation of STAT5 to decreased significantly with increasing concentrations . Yervoy skews the T-cell differentiation towards the Th1/Th17 phenotype which we want.

Another coinhibitor which surpresses the immune resonse is (PD-1) Program Death 1.

Blockade of PD-1 by monoclonal antibodies specific to its ligands (PD-L1 and PD-L2) results in significant enhancement of proliferation and cytokine (gamma interferon [IFN-gamma] and interleukin-2 [IL-2]) secretion by tumor-specific CTLs. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Tregs.

So by do a combinatorial therapy with Yervoy and PD-1 antibodies, It would most likely have a synergistic immune response.



This why on 9-20-2011, Bristol Myer Squibb expanded it's deal with Japan's Ono Pharmaceutical Co. Ltd. BMS now knows that they have an monopoly on T-cell activation and can be applied to many other cancers besides Melanoma. They are collecting the "String of Pearls". It would not surprise me they will go after the rest of the costimulators and coinhibitors on the T-cells. Only time will tell.

My hope is that Bristol Meyer Squibb uses it for the cure of cancer one day and not just monetary gains.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B