Project description:Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression. H2-Aa deficiency, specifically in dendritic cells (DC), led to a quantitative increase in type 2 conventional DC (cDC2) and a decrease in cDC1. H2-Aa–deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition, which had no therapeutic effect by itself. Our findings suggest that inhibiting MHC-II may be an effective immunotherapeutic approach to enhance immune responses to cancer.
Project description:Previous studies suggested the presence of MHC class II-reactive CD8+ T cells in humans and animals, but little is known about their identity, development and function. In this study, we discovered a group of CD8+ T cells bearing T cell receptors (TCRs) reactive to both MHC I and II molecules in MHC II-deficient mice. We cloned their TCRs and analyzed their development and function. In wild type animals, thymocytes bearing those TCRs were purged by negative selection. In the absence of MHC II, they developed into CD8+ T cells and entered the peripheral T cell pool. When encountering MHC II in the periphery, they underwent robust activation and proliferation, attacked self-tissues, and caused lethal autoimmune diseases. In adoptive T cell therapy, CD8+ T cells bearing those TCRs were able to efficiently control MHC II-expressing tumors. This study opens the door to investigate dual-reactive CD8+ T cells, their development and selection in the thymus, and the peril and promise when their normal development and selection are compromised.
Project description:For many cancers, including head and neck squamous cell carcinoma (HNSCC), response rates to immunotherapy remain modest, with limited ability to predict responders. Previous studies that characterized cellular changes associated with immunotherapy in HNSCC focused on immune cells, providing limited insight into malignant cell responses. Motivated by this gap, we performed single cell RNA-sequencing on 16 HNSCC patients pre- and post-neoadjuvant pembrolizumab treatment. We identified a malignant-interferon (IFN)/MHC-II program in malignant cells, characterized by expression of MHC-II and interferon response genes, which was associated with tumor response to pembrolizumab. We validated malignant cell MHC-II expression at the protein level and characterized its relationship with surrounding immune subsets via multiplexed immunofluorescence. In a murine HNSCC model, IFN-γ-induced malignant cell MHC-II expression marked tumors with favorable immune microenvironments and sensitivity to immunotherapy. Finally, we confirmed pre-treatment expression of the malignant-IFN/MHC-II program as marker of response through deconvolution of bulk RNA-seq data from an independent cohort of 25 pembrolizumab-treated HNSCC patients. Beyond identifying malignant cell MHC-II expression and the malignant-IFN/MHC-II program as potential biomarkers for immunotherapy response in HNSCC, our work provides additional insights into the specific and important role of malignant cells in immunotherapy.
Project description:Immunotherapy has revolutionized the landscape of cancer treatment. However, both primary and acquired resistance to immunotherapy, emerged during the co-evolution of cancer cells and the tumor microenvironment (TME), commonly restrain long-term tumor control. In exploring the oncogenic activity of Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), we unexpectedly discovered that this epigenetic regulator exhibits altered expression and aberrant cytosolic localization in cancerous tissues. Cytoplasmic translocation of UHRF1 is induced by its phosphorylation on a specific serine in response to signals provided by factors present in the TME, such as TGF-, enabling UHRF1 to bind MHC-I and promote its ubiquitination and degradation via the E3 activity of UHRF1. Down-regulation of MHC-I results in suppression of the antigen presentation pathway to establish a non-T cell-inflamed TME favoring tumor growth. Genetic deletion of UHRF1 synergizes with immune checkpoint blockade (ICB) treatment and induces an anti-tumor memory response by evoking low-affinity T cells upon sustained UHRF1 inactivation. Our study unveils a novel function of UHRF1 in cancer immune evasion and provides a potential target to synergize with immunotherapy and overcome immunotherapeutic resistance.
Project description:Immune checkpoint inhibitors benefit only a subset of patients, necessitating the development of new sensitizing agents strategies to improve tumor response and efficacy. Major histocompatibility complex class I (MHC-I), vital for tumor antigen presentation and cytotoxic T cell activation, has been an important target of immunotherapy. Nonsense-mediated RNA decay (NMD) is a highly conserved surveillance system that targets mRNAs with premature termination codons (PTCs) and monitors the quantity of about 10% of unmutated mammalian mRNAs. Tumor cells with aneuploidy heavily rely on NMD to compensate the imbalanced DNA levels and lower their antigenicity for immune evasion, making them sensitive to NMD inhibitors. Using an unbiased genome-wide analysis, we unexpectedly identified LTO1/YAE1 complex as novel NMD factors. LTO1/YAE1 complex and its downstream target for iron-sulfur cluster transfer, ABCE1, are widely overexpressed and negatively associated with immune cells infiltration in multiple cancer types. The RNA-sequencing results from these three genes led to the discovery that In tumor cells,compromised NMD is associated with MHC-I upregulation via increased expression of NLRC5, IRF1 and NF-κB in tumor cells. Importantly, we found that low doses of iron chelators, NMD inhibitors in clinical use in treatment of iron overload mimic , enhance MHC-I expression and improvingthese effects and improves immune checkpoint blockade (ICB) efficacy. Our findings suggest that LTO1/YAE1/ABCE1 could be a therapeutic target to enhance cancer immunotherapy by upregulating MHC-I and promoting immune infiltration. Our workfindings links NMD toand iron homeostasis andto the tumor immune microenvironment. Our findings suggest that , highlighting that targeting the NMD could be a therapeutic strategy promote immune infiltration, potentially enhancing cancer immunotherapy.
Project description:Immunotherapy has revolutionized the landscape of cancer treatment. However, both primary and acquired resistance to immunotherapy, emerged during the co-evolution of cancer cells and the tumor microenvironment (TME), commonly restrain long-term tumor control. In exploring the oncogenic activity of Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), we unexpectedly discovered that this epigenetic regulator exhibits altered expression and aberrant cytosolic localization in cancerous tissues. Cytoplasmic translocation of UHRF1 is induced by its phosphorylation on a specific serine in response to signals provided by factors present in the TME, such as TGF-, enabling UHRF1 to bind MHC-I and promote its ubiquitination and degradation via the E3 activity of UHRF1. Down-regulation of MHC-I results in suppression of the antigen presentation pathway to establish a non-T cell-inflamed TME favoring tumor growth. Genetic deletion of UHRF1 synergizes with immune checkpoint blockade (ICB) treatment and induces an anti-tumor memory response by evoking low-affinity T cells upon sustained UHRF1 inactivation. Our study unveils a novel function of UHRF1 in cancer immune evasion and provides a potential target to synergize with immunotherapy and overcome immunotherapeutic resistance.
Project description:The current immunotherapy is effective, but many cancer patients do not respond. The loss of major histocompatibility complex class I (MHC-I) molecules has been proposed as a mechanism by which cancer cells evade tumor-specific T cells in Immune Checkpoint Inhibitor (ICI)-refractory patients. Nevertheless, how cancer cells downregulate MHC-I is poorly understood. We report here that membrane-associated RING-CH-type finger 8 (MARCHF8), upregulated by human papillomavirus (HPV), ubiquitinates and degrades MHC-I proteins in HPV-positive head and neck cancer (HPV+ HNC). MARCHF8 knockdown restores MHC-I levels on HPV+ HNC cells. We further reveal that Marchf8 knockout significantly suppresses tumor growth and increases the infiltration of natural killer (NK) and T cells in the tumor microenvironment (TME). Furthermore, Marchf8 knockout markedly increases the cytotoxic NK cells and CD8+ T cells and their crosstalk with macrophages and enhances the tumor cell-killing activity of CD8+ T cells. CD8+ T cell depletion in mice abrogates Marchf8 knockout-driven tumor suppression and NK and T cell infiltration. Interestingly, Marchf8 knockout, in combination with anti-PD-1 treatment, synergistically suppresses tumor growth in mice bearing ICI-refractory tumors. Taken together, our finding suggests that MARCHF8 could be a promising target for novel immunotherapy for HPV+ HNC patients.