Question

Immune checkpoint blockade – using antibodies that block PD-1 and/or CTLA-4 – is revolutionizing the treatment of many cancers, particularly metastatic cancers. However, a large number of patients do not respond to checkpoint blockade, and resistance to checkpoint therapies is not well understood. One characteristic of patients that often respond well to these therapies is the presence of a ‘hot’ tumor microenvironment, meaning the tumors of these patients are in a more pro-inflammatory state (e.g. high in tumor antigen-specific CTLs and low in immunosuppressive regulatory T cells). Due to this observation, researchers are attempting to turn ‘cold’ tumors hot in conjunction with immune checkpoint blockade by increasing inflammation in the tumor microenvironment. One approach to do so is by activating STING (Stimulator of Interferon Genes), an intracellular pattern recognition receptor for cyclic DNA. STING activation triggers a robust and multi-faceted Interferon response leading to increased tumor immunogenicity and improved anti-tumor immunity.

c. Other Pattern Recognition Receptors beyond STING are also being leveraged to enhance anti-tumor immunity. Name three PRRs from different cellular compartments (i.e. each one you mention must be from a separate cellular compartment), what molecule they recognize, and what type of immune response they induce.

Answer 1

TLR3 is a PRR found in endosome and it is involved in the recognition of dsRNA from viruses and the synthetic dsRNA analogue poly(

RIG-I is a RLR found in cytoplasm and recognizes ssRNA that has a triphosphate moiety in its 5′-terminus it general function is to detect viral replication.

NLRP3 is an RLR which responds to a range of DAMPs, such as necrotic cells, uric acid, ATP, biglycan and hyaluronan and in responce it activates the caspase-1-dependent inflammasome

RAGE is a transmembrane receptor responsible for the recognition of endogenous ligands generated upon cell death and tissue injury.

Dectin-1 is a CLR family receptor which recognizes β-glucans, the major fungal cell wall component, and zymosan. It generates pro inflammatory cytokinin.