Surrogate Markers for Ipilimumab-Treated Patients
Martens and colleagues describe changes in circulating immune cells in metastatic melanoma patients treated with ipilimumab, a CTLA-4 inhibitor, and the impact on clinical outcome. Routine blood counts of T cells, Tregs, and MDSCs were performed in an international cohort of 82 melanoma patients. Changes in absolute lymphocyte counts, CD4+ T cells, and CD8+ T cells were associated with overall survival and clinical response. Increases in all three cell populations identified patients with excellent outcome. These changes reflect the positive mode of action of ipilimumab, underline the importance of the specific T cell response for immunologic tumor control, and represent surrogate marker candidates for outcome.
Novel HER2 Mutations and HER2-Targeted Therapies
Somatic mutations in the tyrosine kinase domain of HER2 may be an alternative mechanism to HER2 activation and affect breast cancer sensitivity toward HER2-targeted therapies. In this study by Zuo and colleagues, 1,248 primary tumors and 18 paired metastatic samples were sequenced for HER2 mutations. Functional analysis found that HER2 negative breast cancer with novel activating mutations may benefit from HER2-targeted therapies, while HER2-positive tumors harboring novel resistance mutations did not. These findings will help illustrate the potential clinical implications of HER2 somatic mutations and assist in identifying patients who would benefit from HER2-targeted therapies in choosing the most beneficial treatment.
Immunomodulatory Drugs Reactivate Lytic EBV
Lenalidomide, thalidomide and pomalidomide (LTP) are immunomodulatory agents for the treatment of multiple myeloma; however, they may increase the incidence of secondary primary malignancies, particularly with lenalidomide use in the maintenance setting. Jones and colleagues show that LTP are able to stimulate the Epstein-Barr virus (EBV) lytic cycle, both in vitro and in vivo, primarily by activating phosphoinositide 3-kinase signaling. This provides a potential mechanism through which use of LTP in immunocompromised patients could promote the development of EBV-associated malignancies, such as Hodgkin disease, through immune suppression, and could also provide a new approach for EBV-related cancers in combination with ganciclovir.
Pancreatic Stellate Cells Regulate Lumican Secretion
Lumican is an extracellular matrix protein whose presence with primary pancreatic ductal adenocarcinoma (PDAC) tumors is associated with improved patient outcome. Kang and colleagues find that activated pancreatic stellate cells isolated from primary PDAC tumors secrete large amounts of lumican that augment adhesion and migration of activated pancreatic stellate cells in a collagen-rich environment. TGF-β inhibits lumican transcription and secretion in activated stellate cells through its canonical signaling pathway and binding of SMAD4 to novel SMAD-binding elements. These findings underscore the influential role of lumican within the stroma of localized PDAC and its impact on tumor biology and patient outcome.
- ©2016 American Association for Cancer Research.