Short answer: CMV () infects most human beings at some point in their life. Human anti-CMV T cell responses are thus a convenient in vitro antigen-specific tool to assess checkpoint inhibitor mAb (monoclonal antibody) functional capability, specifically, whether they function as they should and thus by extension, could reverse human cancer antigen-specific T cell inhibition.
Slightly longer answer
Brief Explanation For Rationale Of Checkpoint Inhibitors
Activated T cells express the PD-1 molecule on their surface. T cell PD-1 binding to PD-L1 expressed by other cells sends an inhibitory signal into the T cell. Such T cells stop proliferating and secreting cytokines, meaning PD-1-PD-L1 binding essentially inhibits T cell effector function.
Many cancer cells highly express PD-L1. Checkpoint inhibitor mAbs that selectively target PD-1 (and ) and PD-L1 ( ) molecules prevent PD-1-PD-L1 interaction. This is akin to releasing the brakes off of previously activated and presently inhibited T cells.
Checkpoint inhibitors used inimply cancer antigen-specific T cells exist but are inhibited by molecules such as PD-1 and CTLA-4 and that blocking them releases the full tumor-killing potential of such T cells. Checkpoint inhibitors unblock other T cells as well, meaning autoimmunity and other tissue pathologies are also possible.
CMV Recall Assay To Assess Functional Capability Of Checkpoint Inhibitor mAbs
A checkpoint inhibitor mAb such as anti-PD-1 Nivolumab can bind PD-1 expressed by any T cell. How to assess if such binding did indeed lift the brakes off of that T cell as it should? Knowing a T cell’s antigenic specificity makes it a piece of cake to assess changes in its responsiveness. For example, in basic immunology, often experiments are done with genetically engineeredtransgenic mice having T cells with a single known, i.e., monoclonal, antigenic specificity. The antigenic peptide specificity of all the T cells in such a mouse is the same. Just culture such T cells with APCs ( ) pulsed with the antigenic peptide they’re specific for in the presence or absence of a checkpoint inhibitor mAb.
Obviously, this is far from feasible for assessing human T cell responses. What type of antigen could then be used to assess functional alterations in human T cell responsiveness? This is especially an issue when using checkpoint inhibitor mAbs in cancer immunotherapy, where cancer-specific T cell antigens often remain unknown. How to confirm functional capability of checkpoint inhibitor mAbs, confirm that a new batch can lift the brakes off of previously activated but currently inhibited T cells as it should? That’s where in vitro assays such as the non-antigen-specific MLR (), SEB ( ) stimulation and the antigen-specific CMV recall assay enter the picture.
- Chronically infects most human beings at some point in their life ( ).
- Estimated ~60% and ~90% US prevalence in those >/=6 and >/=80 years of age, respectively, from 1988 to 1994 ( ).
- Elicits strong T cell immune responses and plenty is known about the features of effective human anti-CMV immunity ( ).
- For example, CMV’s pp65 protein is a major target of human CD4 and CD8 T cell responses (4, 5, , , ).
Such features make assessing changes in human anti-CMV T cell responses a handy tool to monitor functional capability of checkpoint inhibitor mAbs. See an example of such assessment below from.
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