Fatal attraction : NK cell migration toward and activity in solid tumors

Abstract

Natural killer (NK) cells play a key role in tumor immunosurveillance due to their ability to induce apoptosis of tumor cells and produce pro-inflammatory cytokines, without prior immune sensitization. In particular, NK cells demonstrate potent anti-tumor immune responses against metastases and hematological malignancies. These characteristics make NK cells attractive for cancer immunotherapy. In contrast to hematological malignancies, however, adoptive transfer of NK cells has so far not provided clinical benefit in patients with solid tumors. Critical barriers in targeting solid tumors include inefficient homing of infused cells to tumor sites and immunosuppression in the tumor microenvironment. In this thesis, I have investigated strategies to improve NK cell migration to solid tumors and explored the immune landscape in patients with renal cell carcinoma (RCC), focusing on NK cells.

In the first part of this thesis, local production of ligands for the chemokine receptor CXCR3 was induced in the microenvironment of melanoma tumors, which enhanced intratumoral localization of infused ex vivo expanded human NK cells in mouse xenograft models, resulting in superior anti-tumor immunity (paper I). Subsequently, we genetically engineered human NK cells to express the chemokine receptor CXCR2, which conferred them with the ability to specifically migrate to recombinant and RCC tumor-derived CXCR2 ligands, enabling improved targeting of tumor cells in vitro (paper II).

In the second part, we performed a comprehensive analysis of immune cell and soluble factor profiles in blood and tumor biopsies of 14 patients with primary RCC, identifying factors important for NK cell migration, activation, and immunosuppression (paper III). We found profound changes in intratumoral NK cell phenotypes compared with those in peripheral blood, with downregulation of the activation receptor DNAM-1 possibly representing a tumor immune escape mechanism. Moreover, we identified low expression of DNAM-1 and PD 1 on intratumoral and circulating NK cells, respectively, as potential biomarkers of disease progression.

In summary, approaches to improve NK cell homing to tumors and a greater understanding of the RCC immune landscape provided in this thesis, will advance the use and increase the success of NK cell-based therapies in patients with solid tumors.