Targeting L-Lactate Metabolism to Overcome Resistance to Immune Therapy of Melanoma and Other Tumor Entities

Although immunotherapy plays a significant role in tumor therapy, its efficacy is impaired by an immunosuppressive tumor microenvironment. A molecule that contributes to the protumor microenvironment is the metabolic product lactate. Lactate is produced in large amounts by cancer cells in response to either hypoxia or pseudohypoxia, and its presence in excess alters the normal functioning of immune cells. A key enzyme involved in lactate metabolism is lactate dehydrogenase (LDH). Elevated baseline LDH serum levels are associated with poor outcomes of current anticancer (immune) therapies, especially in patients with melanoma. Therefore, targeting LDH and other molecules involved in lactate metabolism might improve the efficacy of immune therapies. This review summarizes current knowledge about lactate metabolism and its role in the tumor microenvironment. Based on that information, we develop a rationale for deploying drugs that target lactate metabolism in combination with immune checkpoint inhibitors to overcome lactate-mediated immune escape of tumor cells.

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The Many Facets of CD38 in Lymphoma: From Tumor–Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy

Cells ◽

10.3390/cells9040802 ◽

2020 ◽

Vol 9 (4) ◽

pp. 802 ◽

Cited By ~ 3

Author(s):

Eleonora Calabretta ◽

Carmelo Carlo-Stella

Keyword(s):

Tumor Microenvironment ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Acquired Resistance ◽

Prognostic Significance ◽

Lymphocytic Leukemia ◽

Lymphoid Malignancies ◽

Non Hodgkin Lymphoma ◽

Cd38 Expression ◽

The Many

The CD38 antigen is expressed in several hematological malignancies, and the anti-CD38 monoclonal antibodies Daratumumab and Isatuximab have an established role in the therapy of multiple myeloma. However, data on the therapeutic utility of CD38 targeting in other lymphoid malignancies are limited. In chronic lymphocytic leukemia, the prognostic significance of CD38 expression is well accepted, and preclinical studies on the use of Daratumumab in monotherapy or combination therapy have demonstrated considerable efficacy. In other lymphoproliferative disorders, preclinical and clinical data have not been as compelling; however, CD38 overexpression likely contributes to resistance to checkpoint inhibitors, prompting numerous clinical trials in Hodgkin and non-Hodgkin lymphoma to investigate whether blocking CD38 enhances the efficacy of checkpoint inhibitors. Furthermore, due to its widespread expression in hematological tumors, CD38 represents an attractive target for cellular therapies such as CAR-T cells. The present review discusses current knowledge of CD38 expression and its implications in various lymphoid malignancies. Furthermore, it addresses current and future therapeutic perspectives, with a particular emphasis on the significance of CD38 interaction with immune cells of the tumor microenvironment. Lastly, results of ongoing studies using anti-CD38 antibodies will be reviewed.

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The Abscopal Effect: Could a Phenomenon Described Decades Ago Become Key to Enhancing the Response to Immune Therapies in Breast Cancer?

Breast Care ◽

10.1159/000511431 ◽

2020 ◽

Vol 15 (5) ◽

pp. 443-449

Author(s):

Hans-Christian Kolberg ◽

Oliver Hoffmann ◽

René Baumann

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Antitumor Immune Response ◽

Abscopal Effect ◽

Antitumor Effects ◽

Effective Combination ◽

Immunological Mechanisms ◽

Immune Therapies

Background: The term “abscopal effect” was defined in 1953. In oncology the term is used to describe systemic antitumor effects triggered by local irradiation (nontarget effect). Although the mechanism of the abscopal effect is not completely understood yet, it has been demonstrated that in situ tumor vaccination, and the resulting antitumor immune response, is one of the key factors. Summary: The development of immune therapies has recently led to concepts combining local radiotherapy and immune therapy with the aim of enhancing the response to immune therapy by the immunological mechanisms summarized in the term abscopal effect. This concept has also been investigated in less immunogenic tumors such as breast cancer. Initial data are promising but the hypothesis that the combination of checkpoint inhibitors and local radiotherapy could be an effective combination in breast cancer has to be proven by ongoing trials. Substitution of local radiotherapy by local hyperthermia could be an option in selected cases. Key Messages: Combination of checkpoint inhibitors with local radiation or hyperthermia in breast cancer is a promising approach and could enhance the response rates generated by immune therapy alone through the antitumor immune response initiated by the abscopal effect.

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Mitoxantrone-Loaded Nanoparticles for Magnetically Controlled Tumor Therapy–Induction of Tumor Cell Death, Release of Danger Signals and Activation of Immune Cells

Pharmaceutics ◽

10.3390/pharmaceutics12100923 ◽

2020 ◽

Vol 12 (10) ◽

pp. 923

Author(s):

Teresa Ratschker ◽

Laura Egenberger ◽

Magdalena Alev ◽

Lisa Zschiesche ◽

Julia Band ◽

...

Keyword(s):

Cell Death ◽

Immune System ◽

Immune Cells ◽

Checkpoint Inhibitors ◽

Tumor Therapy ◽

Superparamagnetic Iron Oxide ◽

Dependent Manner ◽

Tumor Cell Death ◽

Immune Therapies

Stimulating the patient’s immune system represents a promising therapeutic strategy to fight cancer. However, low immunogenicity of the tumor cells within an immune suppressive milieu often leads to weak anti-tumor immune responses. Additionally, the immune system may be impaired by accompanying aggressive chemotherapies. We show that mitoxantrone, bound to superparamagnetic iron oxide nanoparticles (SPIONs) as the transport system, can be magnetically accumulated in adherent HT-29 colon carcinoma cells, thereby inducing the same cell death phenotype as its soluble counterpart, a chemotherapeutic agent and prototypic inductor of immunogenic cell death. The nanoparticle-loaded drug induces cell cycle stop, apoptosis and secondary necrosis in a dose- and time-dependent manner comparable to the free drug. Cell death was accompanied by the release of interleukin-8 and damage-associated molecular patterns (DAMPs) such as HSP70 and ATP, which fostered chemotactic migration of monocytes and maturation of dendritic cells. We furthermore ensured absence of endotoxin contaminations and compatibility with erythrocytes and platelets and investigated the influence on plasma coagulation in vitro. Summarizing, with magnetic enrichment, mitoxantrone can be accumulated at the desired place, sparing healthy peripheral cells and tissues, such as immune cells. Conserving immune competence in cancer patients in the future might allow combined therapeutic approaches with immune therapies (e.g., checkpoint inhibitors).

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Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies

Blood ◽

10.1182/blood-2017-09-772632 ◽

2018 ◽

Vol 131 (15) ◽

pp. 1654-1665 ◽

Cited By ~ 26

Author(s):

Anja Mottok ◽

Christian Steidl

Keyword(s):

Hodgkin Lymphoma ◽

Immune Escape ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Treatment Success ◽

Prognostic Models ◽

High Dose ◽

Great Success ◽

Refractory Disease ◽

Classical Hodgkin Lymphoma

AbstractHodgkin lymphoma is considered a prime example of treatment success, with cure rates exceeding 80% using modern combined modality therapies. However, especially in adolescents and young adults, treatment-related toxicity and long-term morbidity still represent persistent challenges. Moreover, outcomes in patients with relapsed or refractory disease remain unfavorable in the era of high-dose chemotherapy and stem-cell transplantation. Hence, there is a high demand for novel and innovative alternative treatment approaches. In recent years, many new therapeutic agents have emerged from preclinical and clinical studies that target molecular hallmarks of Hodgkin lymphoma, including the aberrant phenotype of the tumor cells, deregulated oncogenic pathways, and immune escape. The antibody-drug conjugate brentuximab vedotin and immune checkpoint inhibitors have already shown great success in patients with relapsed/refractory disease, leading to US Food and Drug Administration approval and new trials testing these agents in various clinical settings. The expanding knowledge and understanding of Hodgkin lymphoma biology and disease progression, as well as the development of robust tools for biomarker-driven risk stratification and therapeutic decision making, continue to be fundamentally important for the success of these and other novel agents. We anticipate that the availability and clinical implementation of novel molecular assays will be instrumental in an era of rapid shifts in the treatment landscape of this disease. Here, we review the current knowledge of Hodgkin lymphoma pathobiology, highlighting the related development of novel treatment strategies and prognostic models that hold the promise to continually challenge and change the current standard of care in classical Hodgkin lymphoma.

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Immune Therapy Resistance and Immune Escape of Tumors

Cancers ◽

10.3390/cancers13030551 ◽

2021 ◽

Vol 13 (3) ◽

pp. 551

Author(s):

Barbara Seliger ◽

Chiara Massa

Keyword(s):

Immune Escape ◽

Checkpoint Inhibitors ◽

Adoptive Cell Therapy ◽

Immune Therapy ◽

Immune Surveillance ◽

Therapy Resistance ◽

The Novel ◽

Major Goal ◽

Immune Mediated ◽

Tumor Clearance

Immune therapy approaches such as checkpoint inhibitors or adoptive cell therapy represent promising therapeutic options for cancer patients, but their efficacy is still limited, since patients frequently develop innate or acquired resistances to these therapies. Thus, one major goal is to increase the efficiency of immunotherapies by overcoming tumor-induced immune suppression, which then allows for immune-mediated tumor clearance. Innate resistance to immunotherapies could be caused by a low immunogenicity of the tumor itself as well as an immune suppressive microenvironment composed of cellular, physical, or soluble factors leading to escape from immune surveillance and disease progression. So far, a number of strategies causing resistance to immunotherapy have been described in various clinical trials, which broadly overlap with the immunoediting processes of cancers. This review summarizes the novel insights in the development of resistances to immune therapy as well as different approaches that could be employed to overcome them.

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Immunotherapy in tumors failing check-point inhibitors:the sarcoma example – What we missed and where we are heading

Cancer Breaking News ◽

10.19156/cbn.2017.0045 ◽

2017 ◽

Vol 5 (2) ◽

pp. 22-32

Author(s):

Alessandra Merlini ◽

Francesco Tolomeo ◽

Sara Miano ◽

Lorenzo D’Ambrosio ◽

Dario Sangiolo ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Escape ◽

Checkpoint Inhibitors ◽

Host Immune System ◽

Tumor Immune Escape ◽

Cancer Subtypes ◽

Complex Interactions ◽

Innate Immunity Cells ◽

Antigen Presenting ◽

Shed Light

The introduction of immune checkpoint inhibitors represented a true revolution in the treatment of melanoma and a few other cancer subtypes. Unfortunately, the use of these drugs did not achieve the same beneficial results in other neoplasms, such as soft tissue sarcoma and gastrointestinal stromal tumor. These failures encouraged deeper research into the complex interactions between cancer and host immune system, to try to shed light on the ability of cancer cells to escape immunologic surveillance. Key elements to explain tumor immune escape were found in the tumor microenvironment. The main actors in this complex network are lymphocytes, cytokines and innate immunity cells such as macrophages and antigen presenting cells. Thus, immuno-oncologists are studying the different components of the tumor microenvironment to identify possible new therapeutic targets. In this paper, we summarize the most important aspects of these interactions, and provide an overview of the newer and more promising immunotherapeutic strategies.

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Pancreatic Cancer and Immunotherapy: A Clinical Overview

Cancers ◽

10.3390/cancers13164138 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4138

Author(s):

Florentine E. F. Timmer ◽

Bart Geboers ◽

Sanne Nieuwenhuizen ◽

Madelon Dijkstra ◽

Evelien A. C. Schouten ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Escape ◽

Checkpoint Inhibitors ◽

Synergistic Effects ◽

Oncolytic Viruses ◽

Ductal Adenocarcinoma ◽

Successful Implementation ◽

Cell Therapies ◽

Radio Therapy ◽

Wide Range

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.

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Hacking Pancreatic Cancer: Present and Future of Personalized Medicine

Pharmaceuticals ◽

10.3390/ph14070677 ◽

2021 ◽

Vol 14 (7) ◽

pp. 677

Author(s):

Alessandro Di Federico ◽

Valentina Tateo ◽

Claudia Parisi ◽

Francesca Formica ◽

Riccardo Carloni ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Personalized Medicine ◽

Kinase Inhibitors ◽

Immune Escape ◽

Checkpoint Inhibitors ◽

Wide Spectrum ◽

Comprehensive Overview ◽

Personalized Approach ◽

Immune Escape Mechanisms

Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC.

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Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development

Cells ◽

10.3390/cells10010067 ◽

2021 ◽

Vol 10 (1) ◽

pp. 67

Author(s):

Hsiang-Wei Huang ◽

Cheng-Chih Chang ◽

Chia-Siu Wang ◽

Kwang-Huei Lin

Keyword(s):

Cell Adhesion ◽

Tumor Microenvironment ◽

Adhesion Molecules ◽

Inflammatory Cytokines ◽

Gastrointestinal Cancer ◽

Cell Adhesion Molecules ◽

Immune Cell ◽

Immune Escape ◽

Checkpoint Inhibitors ◽

Cytotoxic T Cells

Gastrointestinal cancer is highly associated with inflammatory processes inducing the release of cytokines from cancer or immune cells, including interferons, interleukins, chemokines, colony-stimulating factors, and growth factors, which promote or suppress tumor progression. Inflammatory cytokines within the tumor microenvironment promote immune cell infiltration. Infiltrating immune, and tumor-surrounding stromal cells support tumor growth, angiogenesis, metastasis, and immunosuppression through communication with inflammatory cytokines and cell adhesion molecules. Notably, infiltrating immune and tumor cells present immunosuppressive molecules, such as programmed death-ligand 1 (PD-L1) and CD80/CD86. Suppression of cytotoxic T cells promotes tumor avoidance of immune surveillance and greater malignancy. Moreover, glycosylation and sialylation of proteins hyperexpressed on the cancer cell surface have been shown to enhance immune escape and metastasis. Cytokine treatments and immune checkpoint inhibitors are widely used in clinical practice. However, the tumor microenvironment is a rapidly changing milieu involving several factors. In this review, we have provided a summary of the interactions of inflammation and cell adhesion molecules between cancer and other cell types, to improve understanding of the tumor microenvironment.

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Targeting Immune Cells in the Tumor Microenvironment of HCC: New Opportunities and Challenges

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.775462 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xiaopei Hao ◽

Guangshun Sun ◽

Yao Zhang ◽

Xiangyi Kong ◽

Dawei Rong ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Immune Cells ◽

Immune Escape ◽

Tumor Therapy ◽

Difficult Problem ◽

Immune Microenvironment ◽

Comprehensive View ◽

Different Types ◽

Tumor Immunosuppression

Immune associated cells in the microenvironment have a significant impact on the development and progression of hepatocellular carcinoma (HCC) and have received more and more attention. Different types of immune-associated cells play different roles, including promoting/inhibiting HCC and several different types that are controversial. It is well known that immune escape of HCC has become a difficult problem in tumor therapy. Therefore, in recent years, a large number of studies have focused on the immune microenvironment of HCC, explored many mechanisms worth identifying tumor immunosuppression, and developed a variety of immunotherapy methods as targets, laying the foundation for the final victory in the fight against HCC. This paper reviews recent studies on the immune microenvironment of HCC that are more reliable and important, and provides a more comprehensive view of the investigation of the immune microenvironment of HCC and the development of more immunotherapeutic approaches based on the relevant summaries of different immune cells.

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