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Project description:Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX2/PGE2/EP2-4 pathway with widely used nonsteroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from nonresponders shortly after treatment and identified acute IFNγ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T-cell activation. Our findings establish the COX2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot. SIGNIFICANCE: Through performing in-depth profiling of mice and human tumors, this study identifies mechanisms by which anti-inflammatory drugs rapidly alter the tumor immune landscape to enhance tumor immunogenicity and responses to immune checkpoint inhibitors.See related commentary by Melero et al., p. 2372.This article is highlighted in the In This Issue feature, p. 2355.
| S-EPMC7611767 | biostudies-literature
Project description:Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX-2/PGE2/EP2-4 pathway with widely used non-steroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to harness the heterogeneity in treatment outcome and distinguish responders from non-responders shortly following treatment. Deep cellular and molecular tumor profiling revealed acute IFN-γ-driven tumor remodeling in responder mice that was also associated with patient benefit to ICB. Crucially, monotherapy with COX-2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of T cells with enhanced effector function. Inhibition of the COX-2/PGE2 pathway in patient-derived tumor fragments from multiple patients and cancer types revealed a similar shift in the tumor inflammatory environment to favor T cell activation. Our findings establish the COX-2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to switch the tumor inflammatory profile from cold to hot and enhance the efficacy of immunotherapy.
2021-09-13 | GSE160788 | GEO
Project description:Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX-2/PGE2/EP2-4 pathway with widely used non-steroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to harness the heterogeneity in treatment outcome and distinguish responders from non-responders shortly following treatment. Deep cellular and molecular tumor profiling revealed acute IFN-γ-driven tumor remodeling in responder mice that was also associated with patient benefit to ICB. Crucially, monotherapy with COX-2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of T cells with enhanced effector function. Inhibition of the COX-2/PGE2 pathway in patient-derived tumor fragments from multiple patients and cancer types revealed a similar shift in the tumor inflammatory environment to favor T cell activation. Our findings establish the COX-2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to switch the tumor inflammatory profile from cold to hot and enhance the efficacy of immunotherapy.
2021-09-13 | GSE160785 | GEO
Project description:Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy
| PRJNA674502 | ENA
Project description:Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ9]
| PRJNA674500 | ENA
Project description:Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ14]
| PRJNA674507 | ENA
Project description:Cancer immunotherapy such as anti-PD-1/anti-PD-L1 immune checkpoint blockade (ICB) can provide significant clinical benefit in patients with advanced malignancies. However, most patients eventually develop progressive disease, thus necessitating additional therapeutic options. We have developed a novel agent, a-TEA-LS, that selectively induces tumor cell death while sparing healthy tissues, leading to increased activation of tumor-reactive T cells and tumor regression. In the current study, we explored the impact of combined a-TEA-LS + ICB in orthotopic and spontaneously arising murine models of mammary carcinoma. We found that a-TEA-LS + ICB led to increased production of pro-inflammatory cytokines that were associated with a reduction in tumor growth and prolonged survival. Together, these data demonstrate the potential utility of a-TEA-LS + ICB for the treatment of breast cancer and provide the rationale for clinical translation of this novel approach.
| S-EPMC9992800 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) therapy is a revolutionary approach to treat cancers, but still have limited clinical applications. Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment (TME) as one major obstacle. The TME, characterized by acidity, hypoxia and elevated ROS levels, exerts its detrimental effects on infiltrating anti-tumor immune cells. Here, we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles (termed as CAT@CaCO3 NPs) as the simple yet versatile multi-modulator for TME remodeling. CaCO3 NPs can consume protons in the acidic TME to normalize the TME pH. CAT catalyzed the decomposition of ROS and thus generated O2. The released Ca2+ led to Ca2+ overload in the tumor cells which then triggered the release of damage-associated molecular patterns (DAMP) signals to initiate anti-tumor immune responses, including tumor antigen presentation by dendritic cells. Meanwhile, CAT@CaCO3 NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype, further enhancing tumor antigen presentation. Consequently, T cell-mediated anti-tumor responses were activated, the efficacy of which was further boosted by aPD-1 immune checkpoint blockade. Our study demonstrated that local treatment of CAT@CaCO3 NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses, inhibiting the growth of treated tumors and distant diseases.
| S-EPMC10660011 | biostudies-literature
Project description:IntroductionAging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors.MethodsFlow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice. Comparisons: aged versus young naïve WT versus interferon-γ KO mice and WT challenged with B16F10 melanoma and treated with αPD-1 or αPD-L1 ICI. We co-cultured young and aged T cells and myeloid cells in vitro and used OMIQ analyses to test cell-cell interactions.ResultsαPD-1 ICI treated melanoma in young and aged hosts, whereas αPD-L1 ICI was only effective in young. We found considerable, previously undescribed age effects on expression of various IC molecules participating in the ICI treatment, including PD-1, PD-L1, PD-L2, and CD80, in distinct organs and in the tumor. These data help explain differential ICI efficacy in young and aged hosts. Host interferon-γ influenced age effects on IC expression in both directions depending on specific IC molecule and tissue. IC expression was further affected by tumor challenge on immune, non-immune, and tumor cells in tumor and other organs. In in vitro co-culture, αPD-1 versus αPD-L1 distinctly influenced polyclonal T cells in young versus aged, suggesting mechanisms for distinct age-related ICI outcomes.ConclusionAge affects IC expression on specific immune cells in an organ- and tissue-specific manner. ICs were generally higher on aged immune cells. High immune-cell PD-1 could help explain αPD-1 efficacy in aged. High co-expression of CD80 with PD-L1 on dendritic cells could help explain lack of αPD-L1 efficacy in aged hosts. Factors other than myeloid cells and interferon-γ also affect age-related IC expression and T cell function, meriting additional studies.
| S-EPMC9980712 | biostudies-literature
Project description:Radiotherapy (RT) mainly elicits antitumor immunity via the cGAS/STING axis for type I interferon (IFN) production. However, dysregulation of cGAS/STING constrains radiotherapy-induced antitumor immunity and type I IFN-dependent cell death and is associated with shorter survival of patients with colorectal cancer (CRC). Due to their tumor tropism, mesenchymal stem cells (MSCs) have shown the potential to deliver therapeutic genes for cancer therapy. Here, we showed that MSCs enhance the sensitivity to RT by inducing TRAIL-dependent cell death and remodel the tumor microenvironment by recruiting CD8+ immune cells to upregulate PD-L1 in the tumor. By engineering MSCs to express CRC-specific soluble TRAIL via adenovirus-associated virus 2 (AAV2), we found that the therapeutic activity of MSC-sTRAIL was superior to that of MSCs alone when combined with RT. Combined treatment with MSC-sTRAIL and RT significantly reduced cell viability and increased apoptosis by inducing TRAIL-dependent cell death in STING-deficient colorectal cancer cells. MSC-sTRAIL directly triggered TRAIL-dependent cell death to overcome the deficiency of the cGAS/STING axis. Moreover, these combination treatments of MSC-sTRAIL and RT significantly remodeled the tumor microenvironment, which was more suitable for anti-PD-L1 immunotherapy. Taken together, this therapeutic strategy represents a novel targeted treatment option for patients with colorectal cancer, especially cGAS/STING-deficient patients.
| S-EPMC9283452 | biostudies-literature