Infectious disease and cancer are intimately intertwined (see this nice review). Our expertise lies at the intersection of bacterial pathogenesis, innate immunity, and cancer. We are leveraging our knowledge of microbial genetics and how pathogens stimulate innate immune receptors to 1) generate improved microbial cancer therapies, 2) develop new small molecule drugs targeting innate immune receptors, and 3) understand fundamental mechanisms by which bacteria can naturally target tumors, and how tumor colonization impacts responses to immunotherapy.
Bacterial pathogens that reside in the host cytosol elicit anti-tumor responses: Intracellular bacterial pathogens are distinctive tools for fighting cancer, as they can proliferate in tumors and deliver therapeutic payloads to the eukaryotic cytosol. Cytosol-dwelling bacteria have undergone extensive preclinical and clinical testing, yet the mechanisms of activating innate immunity in tumors are unclear. We recently reported that phylogenetically distinct species including Listeria, Rickettsia, and Burkholderia elicited anti-tumor responses in poorly immunogenic melanoma and lymphoma in mice (below figures, left 2 panels)(Danielson et al., 2024).
Bacteria + STING agonists elicit potent anti-tumor responses: Although the bacteria required cytosolic access, anti-tumor responses were largely independent of cytosolic innate immune sensors cGAS/STING and instead required TLR signaling. Strikingly, combining pathogens with STING agonists elicited profound, synergistic anti-tumor effects with complete responses in >80% of mice.
Small molecule STING+TLR agonists elicit synergistic anti-tumor responses: Small molecules have regulatory advantages over using live bacteria, which is relevant for clinical translation. We found that small molecule TLR agonists also synergistically enhanced STING agonists (below figure, right 2 panels). The responses required RAG2 but not interferons, and cured mice developed immunity to cancer rechallenge requiring CD8+ T cells. These studies provide a framework for enhancing microbial and small molecule innate agonists for cancer, via co-activating STING and TLRs.
How can we leverage these findings for novel drug discovery? Despite the striking results that STING+TLR agonist combinations elicit profound anti-tumor responses, current clinical trials continue to focus on single arm innate immune agonists. We seek to overcome this with novel small molecules that activate both pathways. In collaboration with our expert organic chemists in Dr. Vy Dong’s group at UCI, we are synthesizing novel anti-cancer drugs that target multiple arms of innate immunity. We’re excited to see that the novel drugs we have synthesized are showing promising anti-tumor effects in vivo.
Mechanisms of tumor targeting by bacteria
Bacterial pathogens preferentially target and reside in tumors, even when they are eliminated from other organs such as livers and spleens. Strikingly, they accumulate to very high numbers in tumors, often +10,000,000 bacteria! This makes distinctive drug delivery vehicles, as they can also be genetically engineered to deliver anti-cancer payloads specifically to tumors. However, key questions about the mechanisms by which bacteria colonize and persist in tumors is remain unanswered.
Listeria monocytogenes is a Gram-positive foodborne pathogen that has been extensively developed for anti-cancer clinical testing, mainly for its ability to access the cytosol and deliver tumor antigens to MHC-I. Previous phase I and II clinical trials demonstrated safety for delivering 10^9 attenuated Listeria to cancer patients. In our recent work, we find that Listeria actually accumulates in high numbers in tumors (see below image of tumor cells (blue DAPI) harboring Listeria (green)). We are currently investigating mechanisms by which Listeria targets tumors.
Tumor microbiomes
Our studies on how bacteria colonize tumors can help us better understand tumor microbiomes. Bacteria naturally colonize human tumors (Nejman et al). Yet, how does this affect the response to therapy? Ongoing work in the lab seeks to understand how tumor microbiomes affect the response to anti-tumor agents, and how altering microbiomes can improve this response.