While our understanding of how the immune system drives immune responses in individual tissues is relatively advanced, our knowledge of how individual tissues regulate systemic immune responses at the organismal level is far less complete. Cancer is a clinically relevant example of this phenomenon; while local immune suppression in the tumor microenvironment (TME) has been well documented, mounting evidence suggests that cancers drive immune dysfunction at an organismal level. However, the molecular and cellular circuits that mediate this process are incompletely understood.
Preclinical mouse models in which both tumor cells and the immune system are readily manipulated present an opportunity to gain mechanistic insight into systemic immunosuppression by cancer. Ongoing work our lab has shown that the systemic immune landscape is remodeled across mouse breast cancer models, with major changes in both adaptive and innate immune cell populations. This immune landscape remodeling inhibits de novo CD8 T cell priming against Listeria monocytogenes (Lm) by inhibiting cDC1 activation. cDC1 function and CD8 T cell priming is restored by IL-1 blockade, but IL-1R signaling in cDC1s or other immune cells is not responsible for this effect. Instead, IL-1R signaling in tumor cells is the key driver of immune dysfunction.
In this poster, I describe our ongoing efforts to elucidate the mechanism by which localized IL-1R signaling in tumors mediates systemic immune dysfunction by modulating cDC1s. Using a multimodal approach encompassing sequencing, high-parameter spectral flow cytometry, and ELISA, I highlight a putative role for defective interferon signaling in suboptimal cDC1 activation. Likewise, I highlight how tumor-induced remodeling of the myeloid compartment steers Lm away from productive infection, potentially limiting CD8 T cell priming. Finally, I outline an in vivo screen which we will employ to identify tumor cell-intrinsic IL-1 signaling-dependent drivers of cDC1 dysfunction.