Research Projects

Esophageal cancer is one of the leading causes of cancer-related death globally, with a poor overall 5-years survival rate. Histologically, esophageal cancer can be divided into two subtypes, adenocarcinoma and squamous cell carcinoma. Esophageal squamous cell carcinoma (ESCC) accounts for most of the newly reported esophageal cancer, and it is considered a more aggressive form than adenocarcinoma (1). Smoking cigarettes, chewing tobacco and poor oral hygiene are the leading culprits of ESCC. Due to growing habit of smoking and chewing tobacco habits in India, ESCC is considered as one of the leading causes of cancer related death in India, especially in northern and northeastern India (2). Despite significant improvement in early detection and personalized treatment strategies including surgery, chemotherapy, radiotherapy, right prognosis for patients with ESCC remain very poor (3). Chemotherapy and immunotherapy remain very viable options, as molecular targeted therapy and immune checkpoints inhibitors being tested in preclinical settings (4). Combination therapy like paclitaxel, carboplatin and radiation has shown some degree of efficacy in curative treatment settings. However, clinical management of esophageal cancer is highly challenging due to intrinsic or acquired resistance (5). To overcome this major challenge, the development of novel combination therapy which can sensitize resistant cells towards treatment is urgently needed. Immunotherapy is a treatment strategy that can aimed to augment anti-tumor immune system, ultimately causing cancer cell death (6). Immune checkpoint inhibitors are the well-known representative of cancer immunotherapy which shows satisfactory outcomes. There are many FDA approved PD-1 and CTLA-4 targeted inhibitors available for ESCC treatment (7). However, a small portion of ESCC patients can benefit from this treatment because of growing resistance towards these immune check point inhibitors (8). Moreover, tumor cells also can evade immunosurveillance which makes window opportunities of these inhibitors even narrower (9). Therefore, alternative ways to activate anti-tumor immunity in tumor microenvironment would be an absolute necessary. Immunotherapy modulates both innate and adaptive immunity, although innate immunity plays a critical role in recognizing tumor (10). Interestingly, a less explored STING innate immunity pathway gained lot of attention these days. Extranuclear DNA, whether extracellular or intracellular in origin, can activate either the cGAS-STING or DDX41-STING pathway. Activation of STING pathway leads to cytokine synthesis which targets tumor cells (11, 12). Activation of STING triggers robust immune responses, however, presence of three prime repair exonuclease 1 (TREX1) in cytoplasm can severely affect this activation (13). Cancer chemotherapy can cause significant DNA damage; however, cancer cells acquire DNA damage repair mechanisms as a process to become drug-resistant (14). Cancer cells also upregulated TREX1 to counter damaged DNA which can undermine cGAS-STING and DDX41-STING pathway activation (15). Accumulated evidence over the past few years suggested that TREX1 plays a critical role in various types of cancer drug resistance (16). However, the exact mechanism of its cross-talks with STING pathway remains unclear. Also, how cancer cells switch between cGAS-STING and DDX41-STING pathway or whether these pathways work synergistically to target tumor cells are largely unknown. Therefore, the aim of this study is to explore the role of TREX1 in less studied cancer variants like esophageal cancer and its crosstalk with cGAS-STING and DDX41-STING pathway in activating innate immunity. We will also explore and compare the potentiation of combination therapy like targeting cGAS-STING or DDX41-STING pathway by agonist and TREX1 antisense-oligo in esophageal cancer.