Exploiting cell death pathway deficiencies to predict and enhance anti-cancer immune responses

Cancer immunotherapy has gained a lot of momentum in recent years, largely due to the development of immune checkpoint inhibitors such as anti-CTLA4 and anti-PD-1/PD-L1.

The tremendous successes of cancer immunotherapy, showing curative potential in disseminated and intractable tumors, have demonstrated the power of anti-tumor T cells to alter the outcome of metastatic disease and are transforming the treatment of multiple cancer types.

However, most patients do not respond to the blockade of these immune checkpoints, often because their tumors are less immunogenic and do not elicit a sufficient immune reaction.

We hypothesize here that dysfunctions in the apoptotic cell death pathway (caspase deficiency) could lead to more robust anti-cancer immune responses.

Our exciting preliminary findings suggest that caspase deficiency can be measured with our novel BCP assay and is likely an important and currently unappreciated determinant of clinical responses to checkpoint inhibitors.

Our proposal will identify the mechanisms that drive this phenotype in cancer cells and establish the therapeutic potential of modulating caspase proficiency by targeting components of the pathway downstream of apoptosis initiation but upstream of apoptosis execution (e.g. by inhibiting APAF-1) to broaden the effective use of these paradigm-shifting cancer therapeutics.