DNMT1 targeting is established as a promising strategy to counteract CD8⁺ T cell exhaustion and potentiate ICI efficacy and enhances the effector function of melanoma patient-derived tumor infiltrating lymphocytes after prolonged ex vivo expansion.
A complementary therapeutic strategy is discussed: engineering T cells for greater durability in the TME through knockout of exhaustion-associated transcription factors, and reprogramming tumour cells with DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors to restore immunogenicity.
L. Saltis, Liew Jun Mun· Pathology, Research and Prac...· 0 citations
An epigenetic approach is described that facilitates the reversal of repressive DNA methylation and is used to alter the fate of T cell subsets for immunotherapy and is now used to alter the fate of T cell subsets for immunotherapy.
A. Norman, Ben Youngblood, Caitlin C. Zebley· Journal of Immunology· 0 citations
Immune aging impairs T cell-mediated tumor control as well as cancer immunotherapy outcomes. The most important drivers of T cell dysfunction in aged tumors remain unknown. We performed single-cell CRISPR screens to identify Dusp5 and Zfp219 as key regulators of CD8+ T cell persistence and effector differentiation within aged tumors. Loss of Dusp5 increased extracellular signal-regulated kinase (ERK) phosphorylation and globally enhanced T cell proliferation. Conversely, Zfp219 deletion induced epigenetic reprogramming and increased expression of cytotoxic molecules, enhancing antitumor immunity specifically in aging. Levels of the human ortholog ZNF219 were higher within intratumoral CD8+ T cells from older cancer patients, which correlates with worse survival following immunotherapy. Zfp219 ablation synergized with immune checkpoint inhibitors to expand effector-like CD8+ T cells, leading to tumor clearance in aged mice. Our findings highlight Dusp5 and Zfp219 as critical drivers of age-related T cell dysfunction that can be targeted to rejuvenate antitumor immunity in older cancer patients.
Alex C. Y. Chen, Keely Y. Ji, C. Yerinde et al.· Cell· 0 citations
Acquired resistance in cancer is a major obstacle to durable response after immune checkpoint blockade (ICB). While interferon (IFN) signaling is frequently linked with effective ICB response, prolonged interferon signaling within cancer cells paradoxically drives immune suppression. In preclinical mouse models of ICB, relapsed tumors possess an altered epigenetic landscape characterized by inflammatory memory domain accessibility maintained by STAT1 and IRF3. Here, we restore ICB response by identifying and targeting pathways that maintain IFN-associated memory and resistance.
Res 499 tumor cells derived from a late-relapse B16 melanoma were manipulated as indicated, flank-injected into C57BL/6 mice, and treated with ICB. Tumors were harvested on day 16 post-implantation for RNA-seq, ATAC-seq, and flow cytometry.
Prolonged exposure of cancer cells to IFN selectively increases the expression of a subset of IFNy stimulated genes, or “memory ISGs”, which are enriched for immune evasive properties. Moreover, persistent IFN signaling induces elevated expression of not only dsRNA-forming endogenous retroelements (EREs), but also of IFN-inducing dsRNA sensors such as MDA5, establishing a STAT1 and IRF3 activating feed-forward loop. Consequently, knock out of MDA5, or pharmacological blockade of IFN and MDA5 signaling via JAK1/2 and TBK1 inhibitors respectively, lowers ERE expression, decreases chromatin accessibility at inflammatory memory loci, and increases ICB sensitivity. Via flow cytometry, we observe that ex vivo JAKi and TBK1i treatment, in a cancer cell intrinsic manner, induces a more stem-like CD8 T cell response following ICB, possibly through improved interactions with myeloid cells. Given emerging clinical data supporting JAK inhibition in ICB-refractory tumors, these findings may suggest additional benefits from targeting TBK1 as well.
Combined JAK and TBK1 inhibition attenuates inflammatory memory associated resistance and enhances ICB efficacy.
Mark Foundation for Cancer Research
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Nathan Dangle, Jingya Qiu, D. Ye et al.· Journal of Immunology· 0 citations
Radiation induces immunosuppressive myeloid cells that drive therapeutic resistance and metastasis. We identify TET2 as a radiation-induced regulator of myeloid-derived suppressor cells whose expression correlates with poor outcomes in advanced lung cancer patients receiving radio-immunotherapy. Following radiotherapy, myeloid-specific Tet2 deletion suppresses tumor progression and redirects monocyte differentiation toward antigen-presenting myeloid-derived activating cells (MDACs), which augment antitumor T cell responses; spatiotemporal mapping shows that this fate program initiates rapidly in the bone marrow. Mechanistically, a radiation-responsive p53-TET2 axis decreases m5C on chromatin-associated RNAs (caRNAs), enforcing immunosuppressive chromatin compaction and silencing interferon signaling, whereas Tet2 loss restores chromatin accessibility and enhances CD8+ T cell cytotoxicity. Pharmacological TET2 inhibition recapitulates this phenotype and augments radiotherapy and PD-L1 blockade to control primary and metastatic tumors. These findings define MDACs as an immunogenic myeloid subset and establish myeloid reprogramming as a strategy to improve radiotherapy-immunotherapy outcomes.
Fei Ji, Lei Zheng, Da-Peng Chen et al.· Cancer Cell· 0 citations
The aged tumor microenvironment can impair antitumor T cell function, but the molecular regulators that become limiting in this setting remain poorly defined. In a recent issue of Cell, Chen and colleagues harness in vivo CRISPR screening to compare the effects of genetic perturbations in tumor-reactive CD8+ T cells across young and aged hosts. The screen reveals that increased T cell persistence or an effector-like transcriptional state does not necessarily translate into improved tumor control and identifies Dusp5 and Zfp219 as distinct functional regulators. DUSP5 broadly restrains ERK-dependent proliferation, and its loss improves tumor control in both young and aged mice. ZFP219, by contrast, preferentially limits cytotoxicity in aged hosts; its deletion increases granzyme expression and improves tumor control specifically in the aged setting. Human tumor datasets show that ZNF219 expression in intratumoral CD8+ T cells increases with age and is associated with poorer clinical outcomes. Moreover, Zfp219 loss enhances the response to PD-1 blockade in aged mice, producing complete tumor clearance in a subset of animals and durable protection after rechallenge. Together, these findings show that host age can reshape the functional consequences of T cell perturbations and reveal age-dependent genetic vulnerabilities with potential therapeutic relevance.
Brian Oh, Corina Amor· Cancer Research· 0 citations
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