Gene Regulation and Therapeutics for Cancer

Surinder K. Batra, Moorthy Palanimuthu Ponnusamy, Surinder K. Batra, Moorthy Palanimuthu Ponnusamy

• Publisher: CRC Press
• Year: 2021
• ISBN:
  9781351778329
• Edition: 1
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

Differential gene regulation and targeted therapy are the critical aspects of several cancers. This book covers specific gene regulation and targeted therapies in different malignancies. It offers a comprehensive assessment of the transcriptional dysregulation in cancer, and considers some examples of transcriptional regulators as definitive oncogenic drivers in solid tumors, followed by a brief discussion of transcriptional effectors of the programs they drive, and discusses its specific targets. Most targeted therapeutics developed to date have been directed against a limited set of oncogenic drivers, exemplified by those encoding cell surface or cytoplasmic kinases that function in intracellular signaling cascades.

CHAPTER
1

Programmed Death 1 Receptor (PD-1)-mediated Immunomodulatory Effects in Pancreatic Cancer

Ashu Shah¹, Catherine Orzechowski¹ and Maneesh Jain^1,2,*

¹ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

² Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal, treatment refractory malignancies that has emerged as the third leading cause of cancer related deaths in the United States. The overall five-year survival rate for PDAC patients is dismally low at 8% with an estimated 55,440 new cases and 44,330 deaths in the year 2018 [1] . Existing therapies for PDAC include chemotherapy, radiotherapy, and radical surgery. However, the failure to diagnose PDAC at an early stage makes the treatment options ineffective in almost 80% of the patients. Even after surgery, recurrence occurs in 80% of the patients. Till now, only five FDA approved drugs and one combination therapy exists for PDAC patients [2]. Chemotherapy combined with radiation has not shown much success in the patients. The reasons attributed to inadequacy of treatment options is complex molecular landscape of pancreatic tumors [2].

Pancreatic cancer is driven by an accumulation of several activating mutations in the oncogene KRAS and inactivating mutations in tumor suppressor genes TP53, CDKN2A (p16), and SMAD4 in the normal pancreatic duct epithelium. Activating KRAS mutations are present in approximately 95% of PDAC cases and is responsible for activation of PI3K-Akt, notch pathway, hedgehog signaling, and STAT3 pathways which are potent drivers of tumor initiation and maintenance. In addition, shortened telomerase, genomic instability and epigenetic alterations play significant roles in the progression of pancreatic cancer [3]. The disease is believed to originate from a spectrum of precursor lesions including pancreatic intraepithelial neoplasms (PanINs), intraductal papillary neoplasm (IPMN), and mucinous cystic neoplasm (MCN) which over several years develop into aggressive PDAC that invades surrounding tissues and metastasize to different organs.

_______________

^*Corresponding author: [email protected]

PDAC is characterized by dense stroma (desmoplasia) comprising pancreatic stellate cells, fibroblasts, vascular, glial, smooth muscle cells, fat cells, epithelial cells, and immune cells along with extracellular matrix (ECM) and extracellular molecules surrounding epithelial cells. PDAC progression is driven by a complex interplay between tumor cells and the surrounding cells of stroma [4].

Immune System in Pancreatic Cancer

PDAC is characterized by infiltration of both innate and adaptive immune cells including monocytes, macrophages (M1, M2), dendritic cells, B cells (B1, B2, B_reg), T cell subtypes (T_eff, T_reg), NK cells and myeloid derived suppressor cells (MDSC). Although the proportion of these immune cells may vary but their number, location, and stage of maturation in the tumor microenvironment, and their ultimate functional differentiation may impact tumor growth and progression [5, 6]. Intricate cross-talk of infiltrating immune cells, with tumor cells and other stromal cells, result in the establishment of a microenvironment rich in immunosuppressive myeloid and lymphoid subtypes [7, 8]. PDAC is enriched in M2 macrophages, neutrophils, CD4⁺ T cells, T_reg and relatively less number of CD8⁺ T cells [9, 10]. Therefore, PDAC has generally been considered as a poorly immunogenic cancer [11]. However, studies in KPC and other pancreatic cancer mouse models have highlighted the sensitivity of pancreatic cancer to CD8⁺ T cell mediated cytotoxicity [12, 13]. Also, recent studies have clustered PDAC patients into three subtypes on the basis of genetic and transcriptional signatures and these subtypes display differences in their immune cytolytic activity suggesting the importance of immune activity in PDAC [14]. Conversely, multiple studies indicate that PDAC is characterized by lesser immune cell infiltration compared to other cancers such as melanoma, NSCLC, and HNSC where immunotherapy has been successful [15–17].

Checkpoint Blockade Receptor Programmed Death-1 Receptor (PD-1) in Pancreatic Cancer

Tumor cells exploit intrinsic mechanisms of immune evasion which include reduced antigen presentation, increased expression of immunosuppressive molecules such as PD-L1 and accumulation of antigen specific T_regs in the tumor microenvironment resulting in immunosuppression [18]. The immune system is characterized by its ability to distinguish between normal cells in the body and tumor cells through the expression of costimulatory and coinhibitory molecules on immune cells called immune checkpoints. These immune checkpoint molecules play a key role in immunoregulation and immune homeostasis through on-off switch mechanisms and protect the host against autoimmunity. However, tumor cells use these checkpoint molecules to protect themselves from an attack by the immune system. One such checkpoint protein, PD-1, is a coinhibitory receptor which is present on conventional T cells in conjunction with other costimulatory and co-inhibitory molecules and is an important regulator of T cell activation. PD-1 operates as off switch to limit T cell activation by interacting with its ligand, PD-L1, present on normal cells. Under inflammatory conditions like cancer, receptor PD-1 overexpression on T cells is congruent with upregulation of its ligand PD-L1 on antigen presenting cells (APC) and tumor cells [19]. The interaction between PD-1 receptor and its ligand PD-L1 leads to suppressed T cell activation and proliferation which promotes an immunosuppressed condition in the inflammatory microenvironment.

Extensive research over the last two decades on dense desmoplastic stroma in PDAC has elucidated the role of the inflammatory milieu in preventing specific and significant immune response within the tumor. Many immunosuppressive mechanisms operate simultaneously in the PDAC microenvironment, thus making PDAC inaccessible to immunotherapy. Nomi et al. investigated, for the first time, the expression of PD-L1 on human pancreatic cancer cells [20] and showed an association of PD-L1 with poor survival outcomes in PDAC patients. This was associated with lesser number of CD8⁺ T cells in tumor infiltrating lymphocytes of patients with increased PD-L1 expression. Higher PD-L1 levels in 51 human PDAC samples have been correlated with tumor growth rather than progression in contrast to other cancers where PD-L1 expression has been shown to be associated with advanced stage of disease [21, 22]. However, these findings need to be validated in studies with a larger cohort of PDAC patients. The importance of PD-1/PD-L1 axis in pancreatic cancer was further evaluated by testing anti-PD-L1 antibody in the Panc02 subcutaneous mouse model. Treatment with anti-PD-L1 antibody after two weeks of tumor development resulted in a significant reduction of tumor growth along with an increase in tumor reactive CD8⁺ T cells infiltration and IFNγ, Granazyme B and perforin secretion in the tumor. Furthermore, combination of anti-PD-L1 antibody with the FDA approved chemotherapeutic drug Gemcitabine resulted in a substantial decrease in tumor growth as compared to gemcitabine treatment alone [23]. Similar results were obtained with anti-PD-L1 and anti-PD-L2 antibodies in a mouse model, with orthotopically implanted Panc02 cells where antibody treatment resulted in significant tumor suppression along with enhanced intratumoral infiltration of IFNγ-pro...