Immune cell profiles of tumor and regional lymph nodes in surgically treated non-small cell lung cancer

Sellmer, Laura (2023): Immune cell profiles of tumor and regional lymph nodes in surgically treated non-small cell lung cancer. Dissertation, LMU München: Medizinische Fakultät

Abstract

In recent years, improved understanding of the interaction between cancer and the immune system has led to the introduction of various immunotherapy approaches, all harnessing the power of the immune system to impede tumor development, growth and spread. The immune system is a vastly complex network and response to a foreign antigen must be launched in a coordinated fashion both locally as well as systemically. In the case of NSCLC, this requires a response in the lung tissue surrounding the tumor as well as the regional lymph nodes. Most previous studies that attempted to characterize this response were limited by investigating only tumor or lymph nodes, and those who investigated both did not include tumor-free lymph nodes. To tackle these caveats, I have composed a diverse cohort of surgically-treated NSCLC patients containing both long- and short-term survivors. I investigated morphological features in tumor and matched tumor-bearing and non-tumor bearing lymph nodes and analyzed their association with survival. I then used these results to inform transcriptomic analyses of these tissues to determine how morphological changes were reflected on a molecular level. In this thesis, I showed that tumor-infiltrating lymphocytes and macrophages are key components of the immune response in the primary tumor and non-tumor bearing lymph nodes. The importance of lymphocytes in immune mediated tumor control is further corroborated by an association between CD4 expression in non-tumor bearing lymph nodes and survival. Based on these results, immune transcriptomics showed a negative impact of immune dysfunction measured by Tumor Immune Dysfunction and Exclusion (TIDE) score on patient survival. When comparing patients with high levels to patients with low levels of immune dysfunction, CD8 expression was significantly higher in patients with lower levels of immune dysfunction. A more in depth analysis explored the relation of the expression of multiple immune cell exhaustion markers and survival. Among these, TIM-3 and PD-L1 were identified as the only markers to be associated with survival in more than one tissue. Overall, this work presented an integrative approach to assessing immune composition and dysfunction. Levels of immune cell exhaustion markers may indicate a dysfunctional immune status and can predict survival after curative surgery in NSCLC. This work provides the basis for further investigation of the clinical relevance of immune cell exhaustion in early-stage NSCLC.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 7. März 2023
• 1. Bericht­erstatter:in: Tufman, Amanda