Increasing chemokine receptor expression on natural killer (NK) cells may be a promising approach to augment the efficacy of adoptive cellular immunotherapies for patients with renal cell carcinoma (RCC), according to Swedish researchers. They report in the Journal for ImmunoTherapy of Cancer that improving NK cell infiltration into RCC tumors appears to be an attractive therapeutic option for improving the success of NK cell–based therapies and improving clinical responses.
Veronika Kremer of the Department of Oncology-Pathology at the Karolinska Institutet and colleagues theorize that in order to increase the success of NK cell–based therapies of solid tumors, it may require maintaining optimal in vivo proliferation and cytotoxic activity by homing NK cells to the tumor site. The researchers note that adoptive NK cell transfer is being employed to treat patients with hematologic malignancies. A barrier to using this treatment in solid tumors appears to be defective homing of the infused NK cells to the tumor site, according to the researchers.
RCC secretes ligands for the chemokine receptor CXCR2, and the researchers hypothesized that infusion of NK cells expressing high levels of CXCR2 could result in better outcomes. The team examined blood and tumor biopsies from 14 patients with primary RCC; 12 were from clear cell RCC patients, 1 from papillary type 2, and 1 from a patient with chromophobe RCC.
For this investigation, primary NK cells were transduced with human CXCR2 using a retroviral system. Retroviral particles containing the pMSGV1-CXCR2 vector were recovered from supernatant of confluent cultures of PG13 packaging cells provided by Patrick Hwu, MD, from the University of Texas M.D. Anderson Cancer Center. Retrovirus containing the vector pMSGV1-NGFR-N, which encodes the human nerve growth factor receptor gene, was used as a control.
The researchers found that they were able to detect higher concentrations of CXCR2 ligands in tumors compared with plasma of RCC patients and that CXCL5 levels correlated with the intratumoral infiltration of CXCR2-positive NK cells. Tumor-infiltrating NK cells from RCC patients expressed lower CXCR2 compared with peripheral blood NK cells, according to the authors.
The study showed that healthy donor NK cells quickly lost their CXCR2 expression upon in vitro culture and expansion. Genetic modification of human primary NK cells to re-express CXCR2 increased their ability to migrate along a chemokine gradient of recombinant CXCR2 ligands or RCC tumor supernatants compared with controls.
The enhanced trafficking resulted in increased killing of target cells. In addition, CXCR2-transduced NK cells obtained increased adhesion properties and formed more conjugates with target cells. The authors concluded that re-expression of CXCR2 through genetic engineering of ex vivo expanded NK cells suggests a novel strategy to improve anti-tumor responses following adoptive transfer of NK cells.