The Santhakumar Manicassamy Lab

Innate control of anti-tumor immune responses 

Lung, breast, and colon cancers account for approximately 50% of cancer-related deaths in Georgia. Lung cancer is the leading cause of cancer death for both men and women, with colorectal cancer ranking second or third. These cancers are highly immunosuppressive, characterized as "cold tumors" with few immune cells and limited response to immunotherapy. They are also resistant to single-agent therapies, often requiring combination or novel approaches to overcome complex immune evasion. Understanding these mechanisms is essential for developing effective treatments. Our research aims to identify new molecular targets that disrupt tumor-induced immune suppression and enhance antitumor immunity. We have found that the immunosuppressive tumor microenvironment (TME) is characterized by elevated levels of Wnt ligands and retinoic acid (RA). Tumors use the Wnt/β-catenin and RA-RXRα pathways to evade immune detection, and patients with high β-catenin and RXRα expression have lower survival rates. Our recent data indicate that disrupting these pathways can convert cold tumors into hot tumors, increasing their susceptibility to immune attack by activating immune cells within the TME. We are investigating whether blocking the Wnt/β-catenin and RA-RXRα pathways with TLR-based adjuvant treatments can enhance and sustain immune responses, thereby improving patient outcomes. These strategies have the potential to significantly impact clinical practice by improving survival rates through more effective, less toxic therapies. Our studies will provide preclinical evidence that the Wnt/β-catenin and RA-RXRα pathways are promising targets for inducing robust immune responses against lung, breast, and colon cancers. 

Modulation of mucosal immune responses by gut microbiota and dietary metabolites.

Our objective is to identify new molecular targets for immune-based therapies in inflammatory bowel disease (IBD) and colorectal cancer (CRC). Preventing and treating these conditions remains a significant challenge in Georgia, where CRC rates are rising, particularly among younger, rural, and minority populations. The gut microbiota and its metabolites are key regulators of local and systemic immune responses. Disruption of commensal balance and loss of immune tolerance contribute to IBD and CRC. We have demonstrated that activating the PPARα and Wnt pathways in innate immune cells enables dietary lipids to regulate gut mucosal immunity and maintain commensal homeostasis. Additionally, we have identified new roles for HCAR1 (GPR81) cell-surface receptors, which respond to bacteria- and diet-derived metabolites, including D- and L-lactate and 3,5-dihydroxybenzoic acid. This pathway is critical for anti-inflammatory responses, oral tolerance, gut homeostasis, and suppression of colon cancer linked to intestinal inflammation. Our current research examines how the PPARα, Wnt, and HCAR1 pathways regulate commensal homeostasis and influence immune responses. These insights will support the development therapies targeting these immune regulatory pathways in IBD and CRC.