Non-classical mechanisms driving therapeutic resistance

Cell death-induced compensatory proliferation and immunosuppression: Most cancer therapies designate cancer cell death as the therapeutic end goal. Intriguingly, our study reveals that cell death-associated release of PGE2 functions as a mitogen, which recruits quiescent cancer stem cells (CSCs) to repopulate residual tumors [Nature 517, 209–213 (2015)]. PGE2 also acts as an inhibitory DAMP to dampen dendritic cell activation, and thus T cell priming [Nature Communications 11, 6299 (2020)]. Studies are underway to further characterize how CSCs interact with the immune microenvironment to modulate resistance to chemo- and immune checkpoint blockade therapy.