Tumor-Independent Host Secretomes Induced By Angiogenesis and Immune-Checkpoint Inhibitors
Abstract
The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. Although TIS can derive from tumor cells directly, nontumor “host” treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral “side effects” of treatment. Here, we describe a comparative transcriptomic and proteomic analysis of host TIS in tissues and plasma from cancer-free mice treated with antibody and receptor tyrosine kinase inhibitors (RTKI) of the VEGF, cMet/ALK, and PD-1 pathways. We found that all cancer therapies elicit TIS independent of tumor growth, with systemic secretory gene change intensity higher in RTKIs compared with antibodies. Our results show that host TIS signatures differ between drug target, drug class, and dose. Notably, protein and gene host TIS signatures were not always predictive for each other, suggesting limitations to transcriptomic-only approaches to clinical biomarker development for circulating proteins. Together, these are the first studies to assess and compare “off-target” host secretory effects of VEGF and PD-1 pathway inhibition that occur independent of tumor stage or tumor response to therapy. Testing treatment impact on normal tissues to establish host-mediated TIS signatures (or “therasomes”) may be important for identifying disease agnostic biomarkers to predict benefits (or limitations) of drug combinatory approaches. Mol Cancer Ther; 17(7); 1602–12. ©2018 AACR.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 01, 2018
- Source ID
- 10.1158/1535-7163.mct-17-1066
Entities
People
- Amanda Tracz
- Christina R. Lee
- John M.l. Ebos
- Melissa Dolan
- Michalis Mastri
- Robert S. Kerbel
- Yuhao Shi
Organizations
- National Institutes of Health
- Roswell Park Alliance Foundation, Roswell Park Cancer Institute
- Roswell Park Comprehensive Cancer Center
- Sunnybrook Research Institute
- United States Department of Defense