Using Epigenetic Therapy to Boost Immunotherapy in Squamous Lung Cancers

Lung cancer is a particularly difficult to treat and heterogeneous disease. Immunotherapies, which can reactivate a patient’s immune system to target cancer cells for destruction, have recently demonstrated great efficacy in some squamous lung cancers. For example, nivolumab and pembrolizumab, which both involve blockade of the PD1/PD-L1 immune checkpoint, are now commonly prescribed to squamous lung cancer patients who have progressed on standard therapies. However, not every squamous lung tumor responds well to immunotherapy, and it is unclear why certain patients respond positively while others do not. The likely cause of differential responses is tumor heterogeneity, which can present in many ways, including heterogeneity of the tumor cells as well as heterogeneity within the tumor cellular microenvironment (non-tumor cells). Inhibitors of epigenetic readers and writers are one way to influence cellular heterogeneity within tumors, which could bolster immunotherapy by changing both tumor cell heterogeneity and microenvironment (FIGURE 1). Epigenetic drugs are particularly attractive because they have the ability to influence numerous downstream pathways. Recently, I published data that the catalytic function of the histone methyltransferase EZH2 is strongly diminished in squamous tumors when compared to its activity in lung adenocarcinoma (FIGURE 2A-B)1. Genetic depletion of EZH2 in tumor cells promoted the squamous lineage fate in a mixed lineage KRAS/Lkb1-null mouse model (FIGURE 2C). Importantly, promotion of this fate includes upregulation of the immunotherapy target PD-L1 (FIGURE 2D). In addition, data suggest EZH2 inhibition could deplete tumor-associated neutrophils (TANs), which heavily infiltrate human and murine squamous tumors and may decrease immunotherapy effectiveness. I hypothesize EZH2 inhibition will lead to more basal-like squamous lineage committed tumor cells and to a decrease in tumor-associated neutrophils, both of which will make PD1/PD-L1 immunotherapy more effective.