Exploiting the kynurenine pathway to combat platinum-resistant non-small cell lung cancer (NSCLC)

Treating NSCLC is complicated by toxin exposure (e.g., veterans and tar pits), resulting in a US federal mandate (PACT law) to improve therapeutic efficacy and precision. We previously reported that cisplatin-resistant (CR) tumors survive via oxidative metabolism and amino acid uptake, reducing immunosurveillance and viable cytotoxic T-cell populations. Also, indoleamine 2,3-dioxygenase-1 (IDO1; tryptophane degrading enzyme) activity was significantly increased in CR cells determined by elevated KYN secretion, resulting in greater immunosuppressive Treg and MDSC populations. We introduced CR and sensitive NSCLC to syngeneic and humanized mice and found increased tumor-infiltrating Treg and MDSC in CR tumor-bearing mice. Inhibiting IDO1 (epacadostat;200mg/kg/day;PO) reduced tumor growth (30%, n=7; p<0.05) in CR-bearing mice but induced the expression of tryptophan 2,3-dioxygenase-2 (TDO2) (alternate tryptophan degrading enzyme). To block TDO2 compensatory expression, we inhibited IDO1&TDO2 with a new-in-class orally bioavailable dual inhibitor (AT-0174;170mg/kg/day;PO); suppressing CR tumor growth (70%, n=7; p<0.005), enhancing CD8+ and NK cells while suppressing Treg and MDSC cells (n=7; p<0.005). Combining AT-0174 and blocking PD-1 led to tumor regression and longer overall survival (p=0.0001), linking metabolism with immune checkpoint inhibition. Dual IDO1/TDO2 inhibition potently reduced tumor growth and enhanced tumor immunosurveillance in CR NSCLC in vivo models. These results may inform: (i) how the KYN pathway can be exploited in treating CR NSCLC, (ii) the future application of immunotherapy, based on an improved understanding of how CRcells evade immune surveillance.