The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Anti PD 1 Response in Patients with Renal Cell Carcinoma
Tumor cell intrinsic metabolic factors, a hallmark of kidney cancer, may contribute to anti PD 1 treatment resistance. This intersection between cancer immunology and metabolism supports an emerging theme of discovery for tumor type specific biomarkers for immune checkpoint blocking therapies. Pretreatment tumor PD L1 expression has been shown to correlate with response to anti PD 1/PD L1 therapies. Yet, most patients with PD L1+ tumors do not respond to treatment. The current study was undertaken to investigate mechanisms underlying the failure of PD 1 targeted therapies in patients with advanced renal cell carcinoma (RCC) whose tumors express PD L1. Formalin fixed, paraffin embedded pretreatment tumor biopsies expressing PD L1 were derived from 13 RCC patients. RNA was isolated from PD L1+ regions and subjected to whole genome microarray and multiplex quantitative (q)RT PCR gene expression analysis. A balance between gene expression profiles reflecting metabolic pathways and immune functions was associated with clinical outcomes following anti PD 1 therapy. In particular, the expression of genes involved in metabolic and solute transport functions such as UGT1A family members, also found in kidney cancer cell lines, was associated with treatment failure in patients with PD L1+ RCC. Conversely, tumors from responding patients overexpressed immune markers such as BACH2, a regulator of CD4+ T cell differentiation, and CCL3 involved in leukocyte migration. These findings suggest that tumor cell intrinsic metabolic factors may contribute to treatment resistance in RCC, thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti PD 1. Cancer Immunol Res; 4(9) 726 33. (c)2016 AACR. See related Spotlight by Ohashi, p. 719.
Cancer Immunology Research