Abstract 5655: Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic cancer
Christine JansonHeiyoun JungLinda ErtlShirley LiuTon DangYibin ZengAntoni KrasinskiJeff McMahonPenglie ZhangIsrael CharoRajinder SinghThomas J. Schall
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Abstract Pancreatic cancer is an aggressive malignancy with a 5 year survival rate of less than five percent. The predominant immune cells infiltrating the tumor microenvironment are monocytes/macrophages, which are reported to support tumor growth by suppressing host immune responses to the tumor. Recruitment of monocytes to various tissues, including tumors, is dependent upon activation of the chemokine receptor CCR2 by one or more of the chemokines CCL2, CCL8 and CCL13. In preclinical and clinical studies, inhibition of CCR2 in pancreatic cancer has shown to decrease tumor progression by blocking recruitment and accumulation of monocytes/macrophages in the tumor microenvironment. Analysis of human pancreatic tumors revealed elevation of both CCL2 and CSF1, which recruit monocytes, as well as the monocyte marker CD14, in advanced pancreatic cancers. Current immunotherapy using checkpoint inhibitors are effective in some tumors, but lack efficacy in immune insensitive cancers, including pancreatic cancer. Here, we report that the inhibition of CCR2 using a small molecule antagonist potentiates anti-PD-1 immunotherapy in a syngeneic, orthotropic mouse model of pancreatic cancer. Our data reveal that blocking CCR2 decreases tumor burden by blocking monocyte infiltration and creating a microenvironment more favorable for CD8 T cells activity, and provide a mechanistic rationale for investigating the combination of a CCR2 antagonist and an immune checkpoint inhibitor in pancreatic cancer. Citation Format: Christine Janson, Heiyoun Jung, Linda Ertl, Shirley Liu, Ton Dang, Yibin Zeng, Antoni Krasinski, Jeff McMahon, Penglie Zhang, Israel Charo, Rajinder Singh, Thomas J. Schall. Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5655. doi:10.1158/1538-7445.AM2017-5655Keywords:
CCR2
Pancreatic tumor
Cancer Immunotherapy
Immune checkpoint
Pancreatic cancer (PaC) is resistant to immune checkpoint therapy, but the underlying mechanisms are largely unknown. In this study, we have established four orthotopic PaC murine models with different PaC cell lines by intra-pancreatic inoculation. Therapeutic examinations demonstrate that only tumors induced with Panc02-H7 cells respond to αPD-1 antibody treatment, leading to significantly reduced tumor growth and increased survival in the recipient mice. Transcriptomic profiling at a single-cell resolution characterizes the molecular activity of different cells within tumors. Comparative analysis and validated experiments demonstrate that αPD-1-sensitive and -resistant tumors differently shape the immune landscape in the tumor microenvironment (TME) and markedly altering effector CD8
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Immunotherapy is a type of cancer treatment that works by harnessing the power of the immunesystem to recognize and attack cancer cells. Unlike traditional cancer treatments likechemotherapy and radiation therapy, which directly target cancer cells, immunotherapy aims toboost the body's natural defenses against cancer. The immune system is a complex network ofcells, tissues, and organs that work together to protect the body against harmful invaders likeviruses, bacteria, and cancer cells. Normally, the immune system is able to recognize and destroycancer cells as they develop, but sometimes cancer cells can evade detection and continue togrow and spread. Immunotherapy works by stimulating the immune system to recognize andattack cancer cells more effectively.
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In the tumor immune microenvironment (TIME), tumor cells interact with various cells and operate various strategies to avoid antitumor immune responses. These immune escape strategies often make the TIME resistant to cancer immunotherapy. Neutralizing immune escape strategies is necessary to overcome resistance to cancer immunotherapy. Immune checkpoint receptors (ICRs) expressed in effector immune cells inhibit their effector function via direct interaction with immune checkpoint ligands (ICLs) expressed in tumor cells. Therefore, blocking ICRs or ICLs has been developed as a promising cancer immunotherapy by reinvigorating the function of effector immune cells. Among the ICRs, programmed cell death 1 (PD-1) has mainly been antagonized to enhance the survival of human patients with cancer by restoring the function of tumor-infiltrating (TI) CD8 + T cells. It has been demonstrated that PD-1 is expressed not only in TI CD8 + T cells, but also in other TI immune cells and even tumor cells. While PD-1 suppresses the function of TI CD8 + T cells, it is controversial whether PD-1 suppresses or amplifies the suppressive function of TI-suppressive immune cells (e.g., regulatory T cells, tumor-associated macrophages, and myeloid cells). There is also controversy regarding the role of tumor-expressing PD-1. Therefore, a precise understanding of the expression pattern and function of PD-1 in each cell subset is important for improving the efficacy of cancer immunotherapy. Here, we review the differential role of PD-1 expressed by various TI immune cells and tumor cells. We focused on how cell-type-specific ablation or blockade of PD-1 affects tumor growth in a murine tumor model. Furthermore, we will also describe how the blockade of PD-1 acts on TI immune cells in human patients with cancer.
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Tumor immune microenvironment (TIME) include tumor cells, immune cells, cytokines, etc. The interactions between these components, which are divided into anti-tumor and pro-tumor, determine the trend of anti-tumor immunity. Although the immune system can eliminate tumor through the cancer-immune cycle, tumors appear to eventually evade from immune surveillance by shaping an immunosuppressive microenvironment. Immunotherapy reshapes the TIME and restores the tumor killing ability of anti-tumor immune cells. Herein, we review the function of immune cells within the TIME and discuss the contribution of current mainstream immunotherapeutic approaches to remolding the TIME. Changes in the immune microenvironment in different forms under the intervention of immunotherapy can shed light on better combination treatment strategies.
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Tumor-derived extracellular vesicles (EVs) are key immune regulators of the tumor microenvironment. They reshape the immune microenvironment and prevent antitumor immune responses via their immunosuppressive cargo, thereby determining cancer responsiveness to treatment. In the immune microenvironment of melanoma, tumor-derived EVs influence tumor progression by regulating innate and adaptive immune responses. Tumor-derived EV-based therapy is a cutting-edge and promising strategy for inhibiting melanoma progression and enhancing antitumor immunity. This review aimed to summarize the regulatory roles of EVs in the immune responses and immunotherapy of patients with melanoma. This paper provided insights into future exploration directions and potential clinical strategies targeting EVs for melanoma treatment.
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Pancreatic cancer is a common malignancy of the digestive system. It is characterized by a high invasiveness, easy metastasis and pronounced resistance to radiation and targeted therapies, which are thought to be related with the immune microenvironment. Cancer cells, pancreatic stellate cells, immune cells and extracellular matrix, all these constitute the immune microenvironment which inhibits the immune response, promotes cancer growth, and helps it escape from immune surveillance. Therefore, immunotherapy should be combined with targeted therapy and surgery in the clinical treatment. Together, immunotherapy could improve the immune microenvironment and establish a long-term anti-tumor immune response, so as to eventually cure pancreatic cancer.
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Pancreatic cancer; Immune microenvironment; Immunotherapy
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Abstract To improve response rate of monotherapy of immune checkpoint blockade (ICB), it is necessary to find an emerging target in combination therapy. Through analyzing tumor microenvironment (TME)‐related indicators, it is validated that BCAT2 shapes a noninflamed TME in bladder cancer. The outcomes of multiomics indicate that BCAT2 has an inhibitory effect on cytotoxic lymphocyte recruitment by restraining activities of proinflammatory cytokine/chemokine‐related pathways and T‐cell‐chemotaxis pathway. Immunoassays reveal that secretion of CD8 + T‐cell‐related chemokines keeps a robust negative correlation with BCAT2, generating a decreasing tendency of CD8 + T cells around BCAT2 + tumor cells from far to near. Cotreatment of BCAT2 deficiency and anti‐PD‐1 antibody has a synergistic effect in vivo, implying the potential of BCAT2 in combination therapy. Moreover, the value of BCAT2 in predicting efficacy of immunotherapy is validated in multiple immunotherapy cohorts. Together, as a key molecule in TME, BCAT2 is an emerging target in combination with ICB and a biomarker of guiding precision therapy.
Proinflammatory cytokine
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Recently, in the field of cancer treatment, the paradigm has changed to immunotherapy that activates the immune system to induce cancer attacks. Among them, immune checkpoint inhibitors (ICI) are attracting attention as excellent and continuous clinical results. However, it shows not only limitations such as efficacy only in some patients or some indications, but also side-effects and resistance occur. Therefore, it is necessary to understand the factors of the tumor microenvironment (TME) that affect the efficacy of immunotherapy, that is, the mechanism by which cancer grows while evading or suppressing attacks from the immune system within the TME. Tumors can evade attacks from the immune system through various mechanisms such as restricting antigen recognition, inhibiting the immune system, and inducing T cell exhaustion. In addition, tumors inhibit or evade the immune system by accumulating specific metabolites and signal factors within the TME or limiting the nutrients available to immune cells. In order to overcome the limitations of immunotherapy and develop effective cancer treatments and therapeutic strategies, an approach is needed to understand the functions of cancer and immune cells in an integrated manner based on the TME. In this review, we will examine the effects of the TME on cancer cells and immune cells, especially how cancer cells evade the immune system, and examine anti-cancer strategies based on TME.
Cancer Immunotherapy
Immune checkpoint
Evasion (ethics)
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Cancer Immunotherapy
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Metabolic disorders and abnormal immune function changes occur in tumor tissues and cells to varying degrees. There is increasing evidence that reprogrammed energy metabolism contributes to the development of tumor suppressive immune microenvironment and influences the course of gastric cancer (GC). Current studies have found that tumor microenvironment (TME) also has important clinicopathological significance in predicting prognosis and therapeutic efficacy. Novel approaches targeting TME therapy, such as immune checkpoint blockade (ICB), metabolic inhibitors and key enzymes of immune metabolism, have been involved in the treatment of GC. However, the interaction between GC cells metabolism and immune metabolism and how to make better use of these immunotherapy methods in the complex TME in GC are still being explored. Here, we discuss how metabolic reprogramming of GC cells and immune cells involved in GC immune responses modulate anti-tumor immune responses, as well as the effects of gastrointestinal flora in TME and GC. It is also proposed how to enhance anti-tumor immune response by understanding the targeted metabolism of these metabolic reprogramming to provide direction for the treatment and prognosis of GC.
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