Quantification of the Tumor immune Stroma (QTiS) and the metabolic checkpoint molecules in pancreatic cancer: comparison between primary and metastatic tumor

Zhang, Tao (2022): Quantification of the Tumor immune Stroma (QTiS) and the metabolic checkpoint molecules in pancreatic cancer: comparison between primary and metastatic tumor. Dissertation, LMU München: Medizinische Fakultät

Abstract

Pancreatic cancer (PC) remains one of the most lethal cancers in the world. Currently, surgical resection is still the most effective treatment for PC, yet it only works for a few early-stage patients. Although multiple efforts have been ongoing to treat metastatic pancreatic cancer, the outcome remains unsatisfactory. Previous studies have shown that immune imbalance within the tumor microenvironment (TME) promotes tumor progression. Furthermore, glucose metabolism is essential to providing energy for tumor growth, progression, and distant metastasis. There have been studies on tumor-infiltrating leukocytes (TILs) and energy metabolism in the TME of pancreatic cancer, while research on metastatic PC is unavailable because of the surgical treatment of metastatic pancreatic cancer. We were fortunate to have this opportunity to study 26 cases of metastatic PC in our institution. Quantification of the tumor immune stroma (QTiS) algorithm was used to quantify seven markers after immunohistochemical staining, including four markers of leukocytes (CD3+, CD8+, CD20+, and CD66b+) and three markers of metabolic checkpoint molecules (HIF-1α, GLUT1, PDHK1). Afterward, differences in tumor-infiltrating leukocytes (TILs) and metabolic checkpoint molecules (MCMs) between primary and metastatic lesions of metastatic pancreatic cancer were analyzed. Furthermore, the correlation between seven staining markers and clinical data, including overall survival (OS) and disease-free survival (DFS), was also analyzed. The results showed that the infiltration of CD3+, CD8+, and CD20+ in PC primary tumors was higher than that in metastatic tumors. High infiltration of CD20+ TILs (p=0.013) in primary tumors of PC correlates with improved overall survival, and high infiltration of CD8+ (p=0.023) in metastatic tumors of PC correlates with improved overall survival. Low level of platelets in blood circulation system associated with improved OS. The density of HIF-1α and PDHK1 in tumor cell area was higher than that in tumor stroma areas of primary and metastatic tumors. Low-density GLUT1 in tumor stroma areas of primary tumors (p=0.009) and metastatic tumors (p=0.01) of PC correlates with improved OS. Notably, in multivariate analysis, CD8+TILs (HR 0.196, 95% CI 0.044-0.872, p=0.032) in metastatic tumors of PC is an independent prognostic factor; and GLUT1 in tumor stromal areas of primary (HR 5.816, 95% CI 1.006-33.624, p=0.049) and metastatic (HR 5.056, 95% CI 1.258-20.324, p=0.022) tumors is independent prognostic factor to metastatic pancreatic cancer. Overall, the present study used the QTiS algorithm to quantify stroma tumor-infiltrating leukocytes in metastatic PC. We extended this method to quantify metabolic checkpoint molecules in tumor cell and stromal areas, efficiently analyzing IHC staining images. Furthermore, we depicted the characters and differences of TILs and MCMs between primary and metastatic lesions of metastatic PC and the correlation between TILs and MCMs with OS and DFS. Our work can contribute to a better understanding of the immune subtypes and energy metabolism in metastatic PC, which could be vital in improving the diagnosis, prognosis, and treatment of advanced PC.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: tumor-infiltrating lymphocytes, TIL, tumor microenvironment, immunoscore, immune cell infiltration, immune infiltrate, immunosuppression, immune response, immune escape, tumor stroma, glycolysis, pancreatic ductal adenocarcinoma, PDAC
• 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: 28. Januar 2022
• 1. Bericht­erstatter:in: Werner, Jens