Exploiting SAMHD1 in Directing Radiation and Immunologic Dynamics

Emory University, Atlanta GA

Investigators

Abstract

PROJECT SUMMARY Immune checkpoint inhibition (ICI) has emerged as a promising approach for breast cancer; however, only about 10-20% of patients will respond due to lack of immunogenicity. Ionizing radiation (IR) damages DNA and activates the immune system, potentiating ICI in breast cancer patients; however, overall response rates are modest, highlighting the need for novel radiation combination strategies to potentiate ICI. SAMHD1 is recognized for its dNTPase activity, which restricts HIV-1 infection and for mutations associated with Aicardi Goutières syndrome. SAMHD1 is also overexpressed in up to 27% of breast cancers. We and others have shown that SAMHD1 has a novel dNTPase-independent function in governing resistance to IR. SAMHD1 promotes DNA end resection to facilitate DNA double-strand break (DSB) repair through the recruitment of CtIP to DSBs and resection of nascent DNA at stalled replication forks by stimulating MRE11 exonuclease activity. The resection function of SAMHD1 prevents the accumulation of cytosolic DNA that activates cGAS-STING to induce IFN-I expression critical for maturation of dendritic cells and recruitment/stimulation of CD8+ T cells; however, SAMHD1’s role in governing immunologic dynamics underlying anti-tumor immunity is not clear. Our preliminary data indicate that SAMHD1 is highly expressed in triple-negative breast cancer (TNBC) and high SAMHD1 expression is associated with decreased IFN-I signaling, decreased CD8+ T cell tumor infiltration, and poor survival. We have also identified a novel immune niche in TNBC consisting of antigen presenting cells (APC) closely associated with progenitor CD8+ T cells. Progenitor CD8+ T cell differentiation into tumor lytic terminally differentiated effector-like cells (TD) is essential for a robust αPD-1/L1 response. Finally, we developed a novel strategy for the in vivo degradation of SAMHD1 whereby SAMHD1 is targeted with Vpx, a lentivirus accessory protein, packaged in virus-like particles (VLP). We hypothesize that SAMHD1 governs the resistance of breast cancer to IR and ICI at least in part through a dNTPase-independent function in suppressing cytosolic DNA and activation of the innate immune response that potentiates ICI by stimulating progenitor CD8+ T-cells. Targeting SAMHD1 for degradation with VLPs with Vpx sensitizes resistant breast cancer to IR and ICI. We propose to: 1) Determine the molecular mechanism by which SAMHD1 directs radiation and immunologic dynamics underlying response to ICI, 2) Determine the mechanism by which SAMHD1 directs radiation and immunologic dynamics in TNBC patients, 3) Determine if targeting SAMHD1 with VLPs with Vpx sensitizes TNBC tumors to IR and ICI. Completion of this work will define the mechanism by which SAMHD1 directs radiation and immunologic dynamics underlying anti-tumor immunity in breast cancer via stimulation of progenitor CD8+ T cells. This work will also elucidate the significance of SAMHD1 as a potential rationale-driven biomarker for selecting breast cancer patients who may benefit from IR and ICI. Finally, this work will establish proof of concept for the use of VLPs with Vpx in targeting SAMHD1 as a novel approach for overcoming breast cancer resistance to IR and ICI.