Modulation of Type I Interferon Responses to Influence Tumor-Immune Cross Talk in PDAC

Abstract

Immunotherapy has revolutionized the treatment of many cancer types. However, pancreatic ductal adenocarcinomas (PDACs) exhibit poor responses to immune checkpoint inhibitors with immunotherapy-based trials not generating convincing clinical activity. PDAC tumors often have low infiltration of tumor CD8+ T cells and a highly immunosuppressive microenvironment. These features classify PDAC as immunologically “cold.” However, the presence of tumor T cells is a favorable prognostic feature in PDAC. Intrinsic tumor cell properties govern interactions with the immune system. Alterations in tumor DNA such as genomic instability, high tumor mutation burden, and/or defects in DNA damage repair are associated with responses to both immunotherapy and chemotherapy. Cytotoxic or metabolic stress produced by radiation and/or chemotherapy can act as potent immune triggers and prime immune responses. Damage- or stress-mediated activation of nucleic acid-sensing pathways triggers type I interferon (IFN-I) responses that activate innate immune cells and natural killer cells, promote maturation of dendritic cells, and stimulate adaptive immunity. While PDAC exhibits intrinsic features that have the potential to engage immune cells, particularly following chemotherapy, these immune-sensing mechanisms are ineffective. Understanding where defects in innate immune triggers render the PDAC tumor–immune interface less effective, or how T-cell function is suppressed will help develop more effective treatments and harness the immune system for durable outcomes. This review will focus on the pivotal role played by IFN-I in promoting tumor cell–immune cell cross talk in PDAC. We will discuss how PDAC tumor cells bypass IFN-I signaling pathways and explore how these pathways can be co-opted or re-engaged to enhance the therapeutic outcome.

Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy

“…Effector CD8 + TNFRSF9 hi T cells were significantly enriched for TNF-α signaling via the NF-κB, EMT, and apoptosis pathways, whereas effector CD8 + TNFRSF9 lo T cells were enriched for pathways including IFN-γ response, oxidative phosphorylation, and IFN-α response relative to the TNFRSF9 hi cells ( Figure 7E ). These results suggested that increased TNFRSF9 expression in effector CD8 + T cells may lead to a shift in the inflammatory response program, where low expression of TNFRSF9 is associated with an IFN response that is important for cytotoxicity in Teffs ( Cattolico et al, 2022 ), to a TNF-responsive state associated with high expression of TNFRSF9 . Although TNF-α is involved in the CD8 + T cell antitumor activity ( Calzascia et al, 2007 ), it can also promote apoptosis of CD8 + T cells ( Zheng et al, 1995 ).…”

Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival

“…Cytotoxic or metabolic stress induced by chemotherapy and/or radiation can stimulate nucleic acid sensing pathways in both tumor cells and infiltrating immune cells to trigger type-I IFN signaling (INF-α and -β). 107 Type-I IFN is required for robust immune surveillance by directly or indirectly stimulating T-cells, natural killer (NK) cells, or macrophages in the TME. Chemotherapy in combination with immune checkpoint or myeloid inhibitors has shown promise in triggering antitumor immune responses in PDAC, however these responses have not produced durable outcomes.…”

“…Chemotherapy in combination with immune checkpoint or myeloid inhibitors has shown promise in triggering antitumor immune responses in PDAC, however these responses have not produced durable outcomes. 93 , 103 , 107 Tumor mutational status or changes in protein expression may underpin resistance to immunotherapy. Loss of the tumor suppressors STK11, CDKN2A, PTEN, and STING reduction in β2-microglobin are all associated with poor responses to chemotherapy and/or ICIs.…”

“…Loss of the tumor suppressors STK11, CDKN2A, PTEN, and STING reduction in β2-microglobin are all associated with poor responses to chemotherapy and/or ICIs. 107 Homozygous deletion of chromosome 9p21.3 has been identified as a candidate biomarker of immunotherapy resistance in several cancers. 108 Tumors with deletion of 9p21.3 exhibit increased resistance to immune checkpoint inhibitors and altered immune infiltrates.…”

Tumor microenvironment-responsive DNA-based nanomedicine triggers innate sensing for enhanced immunotherapy

“…The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, sensing cytoplasmic double-stranded DNA (dsDNA) of both foreign and self-origin, has been established as an essential mechanism implicated in the innate sensing [ 15 – 17 ]. Briefly, cGAS activated by the cytoplasmic dsDNA, catalyzes the synthesis of 2′-3′ cyclic GMP-AMP (cGAMP) and activates the adaptor protein STING, inducing the production of type I interferons (IFN-Is) and secretion of pro-inflammatory cytokine to trigger the innate immune response [ 18 ]. Growing evidence has indicated that IFN-Is play a key role in promoting the activation and maturation of dendritic cells (DCs), enhancing the antigen presentation for T cell priming, facilitating tumor immune infiltration, and in turn eliciting the anti-tumor immune responses [ 19 ].…”