scholarly journals Chemokines in the Landscape of Cancer Immunotherapy: How They and Their Receptors Can Be Used to Turn Cold Tumors into Hot Ones?

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6317
Author(s):  
Nathan Karin
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Monoclonal Antibodies ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Biological Properties ◽  
Immune Reactivity ◽  
Limited Success ◽  
Program Cell Death

Over the last decade, monoclonal antibodies to immune checkpoint inhibitors (ICI), also known as immune checkpoint blockers (ICB), have been the most successful approach for cancer therapy. Starting with mAb to cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors in metastatic melanoma and continuing with blockers of the interactions between program cell death 1 (PD-1) and its ligand program cell death ligand 1 (PDL-1) or program cell death ligand 2 (PDL-2), that have been approved for about 20 different indications. Yet for many cancers, ICI shows limited success. Several lines of evidence imply that the limited success in cancer immunotherapy is associated with attempts to treat patients with “cold tumors” that either lack effector T cells, or in which these cells are markedly suppressed by regulatory T cells (Tregs). Chemokines are a well-defined group of proteins that were so named due to their chemotactic properties. The current review focuses on key chemokines that not only attract leukocytes but also shape their biological properties. CXCR3 is a chemokine receptor with 3 ligands. We suggest using Ig-based fusion proteins of two of them: CXL9 and CXCL10, to enhance anti-tumor immunity and perhaps transform cold tumors into hot tumors. Potential differences between CXCL9 and CXCL10 regarding ICI are discussed. We also discuss the possibility of targeting the function or deleting a key subset of Tregs that are CCR8+ by monoclonal antibodies to CCR8. These cells are preferentially abundant in several tumors and are likely to be the key drivers in suppressing anti-cancer immune reactivity.

Cancer Immunotherapy-Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

2021 ◽  
Vol 16 ◽  
Author(s):  
Jing Bai ◽  
Ping Liang ◽  
Qian Li ◽  
Rui Feng ◽  
Jiang Liu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Locoregional Therapy ◽  
Incidence And Mortality

: Hepatocellular Carcinoma (HCC) is one of the most common malignancies, the incidence and mortality of which are increasing worldwide. Cancer immunotherapy has revolutionized cancer treatment in recent years. In particular, Immune Checkpoint Inhibitors (ICIs) as new therapeutic tools have demonstrated encouraging antitumor activity and manageable tolerability in HCC. Immunologic checkpoint blockade with antibodies targeting Programmed cell Death-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), and Cytotoxic T Lymphocyte-Associated protein-4 (CTLA-4) strengthens tumor immunity by restoring exhausted T cells. Although the efficacy of combination treatment strategies using ICIs combined with other ICIs, molecular targeted agents, systemic therapy, or locoregional therapy has been well documented in numerous preclinical and clinical studies on several types of cancers, most HCC patients do not benefit from ICI treatment. This review highlights recent developments and potential opportunities related to ICIs and their combination in the management of HCC. The present article also includes recent patent review coverage on this topic.

scholarly journals The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

2021 ◽  
Vol 9 ◽  
Author(s):  
Nádia Ghinelli Amôr ◽  
Paulo Sérgio da Silva Santos ◽  
Ana Paula Campanelli
Keyword(s):  
Cell Death ◽  
Monoclonal Antibodies ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Molecules

Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

scholarly journals Fibroblastic reticular cells predict response to immune checkpoint inhibitors

2020 ◽  
Author(s):  
Daniele Biasci ◽  
James Thaventhiran ◽  
Simon Tavaré
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cancer Immunotherapy ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Reticular Cells

While the role of CD8+ T cells in mediating response to cancer immunotherapy is well established, the role of B cells remains more controversial (1–3). By conducting a large gene expression study of response to immune checkpoint inhibitors (ICI), we show that pre-treatment expression of B cell genes is associated with ICI response independently of CD8+ T cells. However, we discovered that such association can be completely explained by a single gene (FDCSP) expressed outside of the B cell compartment, in fibroblastic reticular cells (FRCs), which form the reticular network that facilitates interactions between B cells, T cells and cognate antigens (4–6) and are required to initiate efficient adaptive immune responses in secondary lymphoid organs (SLO) and tertiary lymphoid structures (TLS) (4, 7). We validated this finding in three independent cohorts of patients treated with ICI in melanoma and renal cell carcinoma. Taken together, these results suggest that FDCSP is an independent predictor of ICI response, thus opening new avenues to explain the mechanisms of resistance to cancer immunotherapy.

scholarly journals Immune checkpoint dysfunction in large and medium vessel vasculitis

2017 ◽  
Vol 312 (5) ◽  
pp. H1052-H1059 ◽  
Author(s):  
Ryu Watanabe ◽  
Hui Zhang ◽  
Gerald Berry ◽  
Jörg J. Goronzy ◽  
Cornelia M. Weyand
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Intimal Hyperplasia ◽  
Cd4 T Cells ◽  
Vessel Wall ◽  
Checkpoint Inhibitors ◽  
Cell Death Protein

Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.

scholarly journals Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
John Apostolidis ◽  
Ayman Sayyed ◽  
Mohammed Darweesh ◽  
Panayotis Kaloyannidis ◽  
Hani Al Hashmi
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
B Cell ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

Cancer cells escape immune recognition by exploiting the programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) immune checkpoint axis. Immune checkpoint inhibitors that target PD-1/PD-L1 unleash the properties of effector T cells that are licensed to kill cancer cells. Immune checkpoint blockade has dramatically changed the treatment landscape of many cancers. Following the cancer paradigm, preliminary results of clinical trials in lymphoma have demonstrated that immune checkpoint inhibitors induce remarkable responses in specific subtypes, most notably classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, while in other subtypes, the results vary considerably, from promising to disappointing. Lymphomas that respond to immune checkpoint inhibitors tend to exhibit tumor cells that reside in a T-cell-rich immune microenvironment and display constitutive transcriptional upregulation of genes that facilitate innate immune resistance, such as structural variations of the PD-L1 locus, collectively referred to as T-cell-inflamed lymphomas, while those lacking such characteristics are referred to as noninflamed lymphomas. This distinction is not necessarily a sine qua non of response to immune checkpoint inhibitors, but rather a framework to move the field forward with a more rational approach. In this article, we provide insights on our current understanding of the biological mechanisms of immune checkpoint evasion in specific subtypes of B-cell and T-cell non-Hodgkin lymphomas and summarize the clinical experience of using inhibitors that target immune checkpoints in these subtypes. We also discuss the phenomenon of hyperprogression in T-cell lymphomas, related to the use of such inhibitors when T cells themselves are the target cells, and consider future approaches to refine clinical trials with immune checkpoint inhibitors in non-Hodgkin lymphomas.

scholarly journals The CD112R/CD112 axis: a breakthrough in cancer immunotherapy

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Taofei Zeng ◽  
Yuqing Cao ◽  
Tianqiang Jin ◽  
Yu Tian ◽  
Chaoliu Dai ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Recent Developments ◽  
Poor Outcomes ◽  
High Level

AbstractThe recent discovery of immune checkpoint inhibitors is a significant milestone in cancer immunotherapy research. However, some patients with primary or adaptive drug resistance might not benefit from the overall therapeutic potential of immunotherapy in oncology. Thus, it is becoming increasingly critical for oncologists to explore the availability of new immune checkpoint inhibitors. An emerging co-inhibitory receptor, CD112R (also called PVRIG), is most commonly expressed on natural killer (NK) and T cells. It binds to its ligand (CD112 or PVRL2/nectin-2) and inhibits the strength with which T cells and NK cells respond to cancer. Therefore, CD112R is being presented as a new immune checkpoint inhibitor with high potential in cancer immunotherapy. CD112 is easily detectable on antigen-presenting or tumor cells, and its high level of expression has been linked with tumor progression and poor outcomes in most cancer patients. This review explores the molecular and functional relationship between CD112R, TIGIT, CD96, and CD226 in T cell responses. In addition, this review comprehensively discusses the recent developments of CD112R/CD112 immune checkpoints in cancer immunotherapy and prognosis.

Immune checkpoint inhibitors in the management of malignancies in transplant recipients

2018 ◽  
Vol 94 (1118) ◽  
pp. 704-708 ◽  
Author(s):  
Dileep Kumar Reddy Regalla ◽  
Grant R Williams ◽  
Ravi kumar Paluri
Keyword(s):  
Monoclonal Antibodies ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Transplant Rejection ◽  
Treatment Strategies ◽  
Therapeutic Benefit ◽  
History Of ◽  
Active Research

Cancer immunotherapy, an area of active research, has thus far yielded several exciting breakthroughs in cancer treatment strategies. So far, immune checkpoint inhibitors have been the most promising method of cancer immunotherapy. CTLA-4, PD-1 and PD-L1 are the immune checkpoint molecules against which monoclonal antibodies act against and revolutionised the treatment of several malignancies. However, it is still unclear whether using these monoclonal antibodies in patients with malignancy and a history of transplant is as beneficial as in patients without a history of transplantation. The reason being, with the therapeutic benefit, also comes the inherent disadvantage of transplant rejection because of the activation of T-cells against donor antigens. So, transplant-related complications limit the usage of the checkpoint blockade therapy to treat malignancies. Here, we review the data published in this context and suggest optimal approaches to using the currently available repertoire of immunotherapies.

scholarly journals Research Progresses in Immunological Checkpoint Inhibitors for Breast Cancer Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Wenxiang Zhang ◽  
Xiangyi Kong ◽  
Bolun Ai ◽  
Zhongzhao Wang ◽  
Xiangyu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Tumor Immune Escape ◽  
Cell Death Protein

Tumor immune escape refers to the phenomenon in which tumor cells escape the recognition and attack of the body’s immune system through various mechanisms so that they can survive and proliferate in vivo. The imbalance of immune checkpoint protein expression is the primary mechanism for breast cancer to achieve immune escape. Cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1)/programmed cell death protein-ligand 1 (PD-L1) are critical immune checkpoints for breast cancer. Immune checkpoint inhibitors block the checkpoint and relieve its inhibition effect on immune cells, reactivate T-cells and destroy cancer cells and restore the body’s ability to resist tumors. At present, immunological checkpoint inhibitors have made significant progress in breast cancer immunotherapy, and it is expected to become a new treatment for breast cancer.

Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

2018 ◽  
Vol 1 (1) ◽  
pp. 28-32
Author(s):  
Piyawat Komolmit
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Immune Checkpoints ◽  
Histocompatibility Complex

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex

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