The aim of this study is to determine the significance of programmed death ligand 1 (PD‐L1 or CD274) methylation in relation to PD‐L1 expression and survival in melanoma. Despite the clinical ...importance of therapies targeting the PD‐1/PD‐L1 immune checkpoint in melanoma, factors regulating PD‐L1 expression, including epigenetic mechanisms, are not completely understood. In this study, we examined PD‐L1 promoter methylation in relation to PD‐L1 expression and overall survival in melanoma patients. Our results suggest that DNA methylation regulates PD‐L1 expression in melanoma, and we identify the key methylated CpG loci in the PD‐L1 promoter, establish PD‐L1 methylation as an independent survival prognostic factor, provide proof of concept for altering PD‐L1 expression by hypomethylating agents, and uncover that PD‐L1 methylation is associated with an interferon signaling transcriptional phenotype. Based on our findings, measuring and altering PD‐L1 promoter DNA methylation may have potential prognostic and therapeutic applications in melanoma.
Immune checkpoint inhibitors (ICI) have significantly improved treatment outcomes for several types of cancer over the past decade, but significant challenges that limit wider effectiveness of ...current immunotherapies remain to be addressed. Certain "cold" tumor types, such as pancreatic cancer, exhibit very low response rates to ICI due to intrinsically low immunogenicity. In addition, many patients who initially respond to ICI lack a sustained response due to T-cell exhaustion. Several recent studies show that epigenetic modifiers, such as SETDB1 and LSD1, can play critical roles in regulating both tumor cell-intrinsic immunity and T-cell exhaustion. Here, we review the evidence showing that multiple epigenetic regulators silence the expression of endogenous antigens, and their loss induces viral mimicry responses bolstering the response of "cold" tumors to ICI in preclinical models. Similarly, a previously unappreciated role for epigenetic enzymes is emerging in the establishment and maintenance of stem-like T-cell populations that are critical mediators of response to ICI. Targeting the crossroads of epigenetics and immune checkpoint therapy has tremendous potential to improve antitumor immune responses and herald the next generation of sustained responses in immuno-oncology.
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis ...in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca2+-NFAT signaling and effector functions by repressing sarco/ER Ca2+-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.
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•Glucose deprivation suppresses anti-tumor T cell effector functions•Glycolytic metabolite PEP sustains Ca2+ and NFAT signaling by blocking SERCA•Ca2+ signaling is an integrator of glycolytic activity and TCR signaling•T cell metabolic reprogramming enhances anti-tumor effector functions
High rates of tumor cell glycolysis suppress intratumoral T cell function by depriving T cells of glucose and the downstream metabolite phosphoenolpyruvate (PEP), which is necessary for maximal Ca2+ -NFAT signaling in T cells. Metabolic rewiring of T cells to generate PEP in glucose-poor conditions improves their anti-tumor responses.
A promising alternative to address the problem of acquired drug resistance is to rely on combination therapies. Identification of the right combinations is often accomplished through trial and error, ...a labor and resource intensive process whose scale quickly escalates as more drugs can be combined. To address this problem, we present a broad computational approach for predicting synergistic combinations using easily obtainable single drug efficacy, no detailed mechanistic understanding of drug function, and limited drug combination testing. When applied to mutant BRAF melanoma, we found that our approach exhibited significant predictive power. Additionally, we validated previously untested synergy predictions involving anticancer molecules. As additional large combinatorial screens become available, this methodology could prove to be impactful for identification of drug synergy in context of other types of cancers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability
. In an effort to identify ...alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials
. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8
T cells, decreasing the prevalence of exhausted CD8
T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1
precursor CD8
T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.
Summary
The remarkable success of immune therapies emphasizes the need for immune‐competent cancer models. Elegant genetically engineered mouse models of a variety of cancers have been established, ...but their effective use is limited by cost and difficulties in rapidly generating experimental data. Some mouse cancer cell lines are transplantable to immunocompetent host mice and have been utilized extensively to study cancer immunology. Here, we describe the Yale University Mouse Melanoma (YUMM) lines, a comprehensive system of mouse melanoma cell lines that are syngeneic to C57BL/6, have well‐defined human‐relevant driver mutations, and are genomically stable. This will be a useful tool for the study of tumor immunology and genotype‐specific cancer biology.
Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with ...previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.
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•Prior ICT is associated with longer PFS of melanoma patients treated with MAPKi•Anti-PD-1/L1 before MAPKi combination prolongs durability of tumor regression•Targeting M2-TAMs augments and CD8+ T cells abolishes priming-associated benefit•Anti-PD1/L1 plus anti-CTLA-4 priming may further control melanoma brain metastasis
Wang et al. couple in vivo preclinical therapeutic testing with temporal single-immune cell and T cell clonotype analysis to identify a sequential-combinatorial regimen and cellular effectors associated with the most durable control of tumor growth and brain metastasis. Initiating immune checkpoint therapy briefly before adding MAPK-targeted therapy may improve patient survival.
Tumors exhibit altered metabolism compared to normal tissues. Many cancers upregulate expression of serine synthesis pathway enzymes, and some tumors exhibit copy-number gain of the gene encoding the ...first enzyme in the pathway, phosphoglycerate dehydrogenase (PHGDH). However, whether increased serine synthesis promotes tumor growth and how serine synthesis benefits tumors is controversial. Here, we demonstrate that increased PHGDH expression promotes tumor progression in mouse models of melanoma and breast cancer, human tumor types that exhibit PHGDH copy-number gain. We measure circulating serine levels and find that PHGDH expression is necessary to support cell proliferation at lower physiological serine concentrations. Increased dietary serine or high PHGDH expression is sufficient to increase intracellular serine levels and support faster tumor growth. Together, these data suggest that physiological serine availability restrains tumor growth and argue that tumors arising in serine-limited environments acquire a fitness advantage by upregulating serine synthesis pathway enzymes.
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•PHGDH expression accelerates mouse models of melanoma and breast cancer•Physiological serine levels can restrain tumor growth in breast cancer•Increased dietary serine levels can accelerate tumor progression•PHGDH expression only benefits tumors in tissues with low serine availability
Nutrient availability can constrain tumor growth. Sullivan et al. demonstrate that in some cancers, physiological levels of the amino acid serine are insufficient to support maximal tumor growth and that melanoma and breast tumors derive a growth advantage by upregulating serine biosynthesis.
Melanoma is a malignant neoplasm of melanocytes that accounts for the majority of skin cancer deaths despite comprising less than 5% of all cutaneous malignancies. Its incidence has increased faster ...than that of any other cancer over the past half-century and the annual costs of treatment in the United States alone have risen rapidly. Although the majority of primary melanomas are cured with local excision, metastatic melanoma historically carries a grim prognosis, with a median survival of 9 months and a long-term survival rate of 10%. Given the urgent need to develop treatment strategies for metastatic melanoma and the explosion of genetic technologies over the past 20 years, there has been extensive research into the genetic alterations that cause melanocytes to become malignant. More recently, efforts have focused on the genetic changes that drive melanoma metastasis. This review aims to summarize the current knowledge of the genetics of primary cutaneous and ocular melanoma, the genetic changes associated with metastasis in melanoma and other cancer types, and non-genetic factors that may contribute to metastasis.
Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion ...molecule, P-selectin glycoprotein ligand-1 (PSGL-1), that is upregulated on responding T cells. PSGL-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector T cells that had downregulated PD-1 as well as other inhibitory receptors. Notably, this response resulted in CD4+-T-cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells inhibited T cell receptor (TCR) and interleukin-2 (IL-2) signaling and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of melanoma cancer in which T cell dysfunction occurs, PSGL-1 deficiency led to PD-1 downregulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology and also functions to regulate T cell responses in the tumor microenvironment.
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•T cell survival was increased in Selplg−/− mice after chronic virus infection•Multi-functional anti-viral T cells in Selplg−/− mice promoted viral control•Ligating PSGL-1 on exhausted CD8+ T cells silenced TCR signals•PSGL-1-deficiency enhanced T cell anti-tumor immunity to melanoma
PSGL-1 is an adhesion molecule known to be important for migration of hematopoietic cells. Bradley and colleagues show that PSGL-1 on T cells dampens TCR signals, limits survival of effector T cells, and promotes immune inhibitory receptor expression, thereby supporting establishment of exhaustion in viral and tumor models.
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