Is the tumor microenvironment immune suppressive? A common interpretation that could very well be flawed. After all, a wide variety of immune cells, ranging from CAF (Cancer-associated fibroblast), TAM,, TAN (Tumor-associated neutrophils), TIL, , to MDSC, , are routinely found within tumors. How could they get in there if tumors suppress immunity?
Rather than non-specifically suppress immunity as steroids do for example, tumors seem to create an immune subversive environment in an attempt to specifically prevent effective anti-tumor immunity.
The fact that tumor-specific TILs are indeed found in tumors implies the immune system does respond to tumor-specific antigens. Such responses are often not effective, the notion being that tumors express and secrete specific molecules that prevent such an outcome. Different interpretations lead to consideration of different treatment approaches.
- If tumors imposed blanket immune suppression then immunotherapies such as checkpoint inhibitors (monoclonal antibodies that target molecules such as PD-1, PD-L1 or CTLA-4) that lift the brakes off of T cells should work in every single instance and yet that’s not the case since so far they only appear to work in subsets of patients.
- Anti-PD-1 mAb should block the suppressive effect of MSDC since they are known to express high levels of PD-1.
- That checkpoint inhibitors don’t work as effectively as envisaged suggests blanket immune suppression within the tumor microenvironment is likely not an accurate interpretation.
- In the CAR T approach, the patient’s own* T cells are harvested, cultured in vitro, genetically engineered to express an antibody-like molecule to specifically target an antigen (protein) expressed on the surface of tumor cells. The process is akin to transforming all sorts of T cells to become tumor-seeking missiles.
Neither approach utilizes the hallmark of T cells, their antigen-specificity.
Theoretically CAR Ts could indeed be engineered to specifically target tumor-infiltrating immune cells thought to impede effective anti-tumor immunity.
MDSC clearly represent important prognostic value in tumors, their presence deemed detrimental in gastric, urogenital, and head and neck cancers but not so in colorectal cancers ().
- In order for CAR Ts to specifically target MDSC requires a MDSC-specific cell surface protein. The few studies to have examined human tumor-infiltrating MDSC in detail thus far report them to be quite heterogeneous ( , ), which implies they may not all express the same cell-surface protein. If that turns out be the case, it would represent a formidable technical challenge to the goal of using CAR Ts to target and eliminate MDSCs.
- There are as-yet no validated antibodies that specifically target human MDSC ( ). Such an antibody is necessary to construct the CAR part of a CAR T cell.
- High tech approaches such as MDSC-targeting CAR Ts may not even be needed. Mouse model studies have shown that , a standard cancer chemotherapy drug, can directly deplete mouse MDSCs ( ). Unknown whether it can do likewise with human MDSCs.
Some mouse model studies have reported using CAR T’s engineered to target fibroblast activation protein (FAP), which is highly expressed on CAFs (, ). Such preliminary studies are proof of concept for such an approach. Do human CAFs also specifically express FAP? Whether such an approach could be practical turns on the answer to such key questions.
* Note that currently biotech and pharma companies are interested in off-the-shelf CAR T cells, i.e., allogeneic rather than derived from the patient’s own T cells, because a personalized approach would be obviously much more expensive.
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