Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade

Abstract

SUMMARY Therapeutic blocking of the PD1 pathway results in significant tumor responses but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways, and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.

Mitotic progression following DNA damage enables pattern recognition within micronuclei

“…B16-F10 STING knockouts were generated as previously described 25 , sgRNA sequences are presented in Table 1. Single cell clones were screened for knockout by adding cGAMP as described below and monitoring ISG induction.…”

“…Volumes were measured using calipers starting at day 11 and calculated using the formula L × W 2 × 0.52, where L is the longest dimension and W is perpendicular to L. Animals are euthanized when either tumor reached 1.5cm in the largest dimension according to IACUC guidelines. Overall survival and flow cytometry for tumor infiltrating CD8+ T-cells was performed as described 25 . For the in situ irradiation experiments of Extended Data 4e and 4f experiments were performed using the Small Animal Radiation Research Platform (SAARP) as previously described 24 .…”

“…anti-CTLA4 antibody) 22–24 , suggesting that local radiation can be immunomodulatory. We have extensively characterized how irradiation of one tumor along with immune checkpoint blockade can produce T cell-dependent responses in the contralateral unirradiated tumor using the B16 syngeneic murine model of melanoma 24, 25 . To examine the dependence of abscopal responses on the cGAS-STING pathway, we used this B16 model and irradiated cells ex vivo (Fig 4a).…”

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

“…Despite ICD induction, the antitumor activity of dinaciclib as a monotherapy was limited, and only in combination with anti-PD1 Ab did dinaciclib enhance tumor suppression (Figure 1, A-C). Recent studies have shown that the induction of PD1 and PD-L1 expression on tumor and associated immune cells can suppress radiation-or chemotherapy-induced immune responses (50,51), and type I IFN signaling plays an important role in mediating PD1 expression on T cells in tumor (52)(53)(54). Similarly, we found increased expression of PD1 on tumor-infiltrating CD8 + T cells after in vivo dinaciclib treatment ( Figure 6A) and increased expression of PD-L1 on tumor cells after in vitro treatment (Supplemental Figure 8).…”

1244 Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

“…Treatment with both aPD-1 and G-1 extended survival dramatically, indicating a marked combinatorial benefit ( Figure 5B-C). Although B16F10 melanoma is the most commonly used model for melanoma immunology studies, and experimental results have largely translated to humans (Benci et al, 2016;Twyman-Saint Victor et al, 2015), B16F10 lacks the Braf or NRas oncodriver mutations present in most Shain et al, 2015). To test whether GPER signaling has similar anti-melanoma activity in a potentially more medically relevant model, we used genetically-defined melanoma cells from the newly-available Yale University Mouse Melanoma collection (YUMM).…”