Fatal Attraction:
NK cell migration toward and
activity in solid tumors
Fatal Attraction:
NK cell migration toward and activity in solid tumors
THESIS FOR DOCTORAL DEGREE (Ph.D.)
Veronika Kremer
ABSTRACT
LIST OF SCIENTIFIC PAPERS
CONTENTS
LIST OF ABBREVIATIONS
1 TUMOR IMMUNOLOGY
1.1 THE IMMUNE SYSTEM IN A NUTSHELL
1.1.1 Innate immunity
1.1.2 Adaptive immunity
1.2 IMMUNITY MEETS CANCER
1.2.1 Anti-tumor immunity
1.2.2 Tumor immune escape
2 NATURAL KILLER CELLS
2.1 NK CELL SUBSETS
2.2 REGULATION OF NK CELL RESPONSES
2.2.1 Inhibitory signaling
2.2.2 Activating signaling
2.3 REGULATION OF NK CELL MIGRATION
2.4 NK CELLS IN TISSUES
2.5 NK CELLS IN CANCER
2.5.1 NK cells mediate anti-tumor immunity
γ leads to reduced metastasis formation [121].
2.5.2 NK cells are negatively regulated in cancer
γ
3 IMMUNOTHERAPY OF CANCER
3.1 IMMUNOMODULATORY ANTIBODIES
3.2 ADOPTIVE CELL THERAPY
3.3 NK CELL THERAPY
3.3.1 NK cell sources and ex vivo expansions
3.3.2 Improving NK cell therapy of solid tumors
3.3.2.1 Enhancing in vivo proliferation and persistence
3.3.2.2 Improving homing to tumor sites
.
3.3.2.3 Reducing suppression in the tumor microenvironment
3.3.2.4 Overcoming inhibition
3.4 RENAL CELL CARCINOMA
4 MAIN RESULTS AND DISCUSSION
4.1 STRATEGIES TO IMPROVE NK CELL MIGRATION TO SOLID TUMORS
4.1.1 Modulation of chemokines in the tumor microenvironment
4.1.2 Modulation of the NK cell chemokine receptor repertoire
4.2 UNDERSTANDING THE NK CELL-ASSOCIATED IMMUNE LANDSCAPE IN RENAL CELL CARCINOMA
4.2.1 Mechanisms of immune escape from NK cells
4.2.1.1 DNAM-1 downregulation
4.2.1.2 CD16 downregulation
4.2.1.3 PD-1 upregulation
4.2.2 Lymphocyte infiltration into RCC tumors
4.3 METHODOLOGICAL CONSIDERATIONS 4.3.1 Xenograft mouse models
4.3.2 Flow cytometry analysis
4.3.3 Multivariate statistical analysis
5 CONCLUSIONS AND OUTLOOK
5.1 CONCLUDING REMARKS
•
•
•
•
5.2 FUTURE DIRECTIONS – THE X FACTOR
