PD-L1 and PD-L2 are expressed on the cell-surface of a much wider variety of cells, being reported not just on T and B cells but also endothelial and epithelial cells, heart, lung, skeletal muscle, placenta, among others (2,). PD-L1 became relevant for cancers when multiple studies reported ( )
- Its high level expression by many types of cancers such as Breast, Cervix, Colon, Esophagus, Liver, Lung, Kidney, Ovary, Pancreas, Skin.
- Its expression by tumors correlated with poorer patient prognosis.
At the same time, multiple studies also correlated high PD-1 expression levels on(TILs) with poor prognosis of cancer patients as well as poor effector function (anti-tumor activity) of such TILs in in vitro studies ( ).
High PD-L1 expression on tumor cells is considered a tumor adaptation attempting to thwart effective anti-tumor immune responses by inhibiting PD-1-expressing TILs. Persistent T cell expression of PD-1 is interpreted as a sign of T cell exhaustion, a colorful description signifying the cell is or has become poorly capable of performing its antigen-specific effector functions.
- In the case of helper CD4 T cells, PD-1 expression implies poor capacity to help B and cytotoxic CD8 T cells perform their effector functions.
- In the case of cytotoxic CD8 T cells, PD-1 expression implies poor capacity to kill their target cells.
The hope behind PD-L1 or PD-1 blockade is doing so would release from inhibition PD-1-expressing cancer-specific T cells present in the tumor (and maybe even anywhere else in the body), and thus render them capable of attacking and ridding of the tumor since blocking PD-1–PD-L1 engagement was found to reverse lymphocyte effector function inhibition, at least in preclinical (mouse model) studies.
Ideally, the most optimal cancer immunotherapy approach would be cancer antigen-specific since they would likely be those with minimal collateral cost. For example, where an immune cell, say a cytotoxic CD8 T cell specific for a cancer cell antigen, bound its target antigen on the surface of a cancer cell and killed it.
Obviously, PD-L1 or PD-1 blockade is a very different process, affecting not just tumor antigen-specific lymphocytes but others as well so it’s not surprising to note then that it specifically and checkpoint inhibitors in general have at least two major drawbacks.
- They are not antigen-specific in the strict immunological sense, i.e., they do not target an antigen expressed only by the tumor but not by healthy cells. Thus there is scope for off-target effects ( ), meaning attack on non-tumor tissue(s) as well. The hope there is that careful application of blockade dose and frequency would help focus the Rx more to cancer cells and help mitigate targeting of healthy tissue cells.
- Tumor-infiltrating and therefore presumably tumor-specific T cells could express not just PD-1 but multiple cell-surface inhibitory receptors such as ( ) and TIM-3 ( ) ( ). Blocking PD-1 alone on such T cells might not suffice to reverse their inhibition. May need to block these other inhibitory molecules as well.
PD-L1 blockade also suffers from an additional drawback, namely, the lack of reliable identification, which means lack of reliable targeting. Identification of PD-L1 expressing cells was mired in technical difficulties since antibodies specific for human PD-L1 had a track record of poor validation. This made it hard to accurately and reliably ascertain whether a particular tumor sample expresses PD-L1 or not. This improved only in recent years after technically validated(IHC) assays using specific anti-human PD-L1 antibody clones such as Dako/BMS clone 28-8, Merck’s mAb clone 22C3, and Ventana (Genentech/Roche) mAb clone SP142 appeared on the scene ( , ).
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