Previously, studying HSCs at scale and across susceptible patient populations is made impossible by the costly, invasive, and impractical nature of collecting bone marrow aspirates/biopsies. In a breakthrough study, we found that rare circulating hematopoietic stem and progenitor cells (cHSPC, 0.05% of PBMC) fully capture the diversity and heterogeneity of their bone marrow counterparts. We pioneered in-depth single cell RNA/ATAC of cHSPC as a surrogate of systemic hematopoietic changes in human disease and defined epigenetic memories that are passed from progenitors to progeny immune cells and their functional relevance. Applying this approach, we were the first to demonstrate durable epigenetic reprogramming of HSPC and functional consequences following a naturally occurring human infection (severe SARS-CoV-2) (Cheong et al. Cell. 2023). We described epigenetic programs that drive persistent myeloid skewing and convey to progeny mature myeloid cells a hyper-responsiveness to stimulation, augmented migratory potential and antigen presentation. We revealed that some of these durable programs are encoded by early, transient IL-6R signalling. We further modeled this in mice and relate these phenotypes to Long COVID. In a complementary study, we found that mild SARS-CoV-2 infection induces epigenetic reprogramming in alveolar macrophages, increasing the activity of type I interferon-related transcription factors and poising of antiviral genes for enhanced secondary responses (Lercher et al. Immunity. 2024). Together, these studies highlight the potential of targeting innate immune memory in HSPC and long-lived tissue resident immune cells in infection.
Next, we were interested in the potential for such mechanisms — epigenetic memory in HSPC — to feature prominently in anti-tumor immunity. The first immunotherapy for cancer was the bacterium Bacillus Calmette-Guerin (BCG), which is still in use as a microbial immunotherapy for early-stage bladder cancer. Despite its longstanding clinical use, its mechanism of action has been unclear. In a recent study, we elucidate the surprising upstream mechanism by which BCG induces anti-tumor immunity and in so doing, provide a general paradigm by which the myeloid compartment can be armed and mobilized via HSPC reprogramming to enhance anti-tumor responses. We demonstrate in both mice and humans that BCG, when administered in the bladder for bladder cancer, colonizes the bone marrow and modifies the transcriptional programs of HSPC, upregulating interferon responsive gene sets, including those involved in antigen presentation (Daman et al. Cancer Cell. 2025). This effect on HSPCs enhances the abundance and function of myeloid progeny, including macrophages, dendritic cells, and neutrophils, which we show preferentially migrate into tumors, more efficiently prime anti-tumor T cell responses, and resist reprogramming by the tumor microenvironment to pro-tumor states. Using bone marrow chimeras reconstituted with HSPCs from mice treated with BCG in the bladder, we show that reprogrammed HSPCs are sufficient to transfer the anti-tumor activity of BCG to recipient animals. Importantly, this effect is not limited to bladder cancer, as we demonstrate that bladder BCG-reprogrammed HSPCs can also transfer to recipient mice the ability to restrict melanoma growth and, excitingly, strongly synergize with PD-1 blockade to clear otherwise treatment refractory tumors. These findings unite several seemingly disparate fields of study. The phenomenon of “trained immunity” or “innate immune memory” has been studied as a mechanism of heterologous protection from infection after HSPC-reprogramming from systemically administered vaccines such as BCG. However, our study indicates that innate immune memory is an integral part of a mucosal-administered immunotherapy previously thought to act locally. More generally, our data indicate that HSPC-intrinsic innate immune memory can mediate anti-tumor immunity, connecting HSPC-reprogramming to mature myeloid cell migration and antigen presentation programs, and ultimately to the anti-tumor T cell response. This highlights the broad potential of harnessing HSPC-reprogramming to enhance anti-tumor immunity.
