Cells

Review

48 pages, 2218 KiB

Open AccessReview

Dendritic Cells: The Long and Evolving Road towards Successful Targetability in Cancer

by Enrica Marmonti, Jacqueline Oliva-Ramirez and Cara Haymaker

Cells 2022, 11(19), 3028; https://doi.org/10.3390/cells11193028 - 27 Sep 2022

Cited by 10 | Viewed by 5051

Dendritic cells (DCs) are a unique myeloid cell lineage that play a central role in the priming of the adaptive immune response. As such, they are an attractive target for immune oncology based therapeutic approaches. However, targeting these cells has proven challenging with [...] Read more.

Dendritic cells (DCs) are a unique myeloid cell lineage that play a central role in the priming of the adaptive immune response. As such, they are an attractive target for immune oncology based therapeutic approaches. However, targeting these cells has proven challenging with many studies proving inconclusive or of no benefit in a clinical trial setting. In this review, we highlight the known and unknown about this rare but powerful immune cell. As technologies have expanded our understanding of the complexity of DC development, subsets and response features, we are now left to apply this knowledge to the design of new therapeutic strategies in cancer. We propose that utilization of these technologies through a multiomics approach will allow for an improved directed targeting of DCs in a clinical trial setting. In addition, the DC research community should consider a consensus on subset nomenclature to distinguish new subsets from functional or phenotypic changes in response to their environment. Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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19 pages, 2970 KiB

Open AccessReview

Clinical and Translational Significance of Basophils in Patients with Cancer

by Jitesh Chauhan, Chara Stavraka, Melanie Grandits, Lais C. G. F. Palhares, Debra H. Josephs, Katie E. Lacy, James Spicer, Heather J. Bax and Sophia N. Karagiannis

Cells 2022, 11(3), 438; https://doi.org/10.3390/cells11030438 - 27 Jan 2022

Cited by 12 | Viewed by 5038

Abstract

Despite comprising a very small proportion of circulating blood leukocytes, basophils are potent immune effector cells. The high-affinity receptor for IgE (FcɛRI) is expressed on the basophil cell surface and powerful inflammatory mediators such as histamine, granzyme B, and cytokines are stored in [...] Read more.

Despite comprising a very small proportion of circulating blood leukocytes, basophils are potent immune effector cells. The high-affinity receptor for IgE (FcɛRI) is expressed on the basophil cell surface and powerful inflammatory mediators such as histamine, granzyme B, and cytokines are stored in dense cytoplasmic granules, ready to be secreted in response to a range of immune stimuli. Basophils play key roles in eliciting potent effector functions in allergic diseases and type 1 hypersensitivity. Beyond allergies, basophils can be recruited to tissues in chronic and autoimmune inflammation, and in response to parasitic, bacterial, and viral infections. While their activation states and functions can be influenced by Th2-biased inflammatory signals, which are also known features of several tumor types, basophils have received little attention in cancer. Here, we discuss the presence and functional significance of basophils in the circulation of cancer patients and in the tumor microenvironment (TME). Interrogating publicly available datasets, we conduct gene expression analyses to explore basophil signatures and associations with clinical outcomes in several cancers. Furthermore, we assess how basophils can be harnessed to predict hypersensitivity to cancer treatments and to monitor the desensitization of patients to oncology drugs, using assays such as the basophil activation test (BAT). Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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22 pages, 4916 KiB

Open AccessReview

Myeloid-Derived Suppressor Cells in Solid Tumors

by Tianmiao Ma, Bernhard W. Renz, Matthias Ilmer, Dominik Koch, Yuhui Yang, Jens Werner and Alexandr V. Bazhin

Cells 2022, 11(2), 310; https://doi.org/10.3390/cells11020310 - 17 Jan 2022

Cited by 39 | Viewed by 8040

Abstract

Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and [...] Read more.

Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and migrate in large quantities during circulation, inhibiting the cytotoxic functions of T cells and NK cells. This process is regulated by ROS, iNOS/NO, arginase-1, and multiple soluble cytokines. The definition of MDSCs and their phenotypes in humans are not as well represented as in other organisms such as mice, owing to the absence of the cognate molecule. However, a comprehensive understanding of the differences between different species and subsets will be beneficial for clarifying the immunosuppressive properties and potential clinical values of these cells during tumor progression. Recently, experimental evidence and clinical investigations have demonstrated that MDSCs have a close relationship with poor prognosis and drug resistance, which is considered to be a leading marker for practical applications and therapeutic methods. In this review, we summarize the remarkable position of MDSCs in solid tumors, explain their classifications in different models, and introduce new treatment approaches to target MDSCs to better understand the advancement of new approaches to cancer treatment. Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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11 pages, 715 KiB

Open AccessReview

Chimeric Antigen Receptors Expand the Repertoire of Antigenic Macromolecules for Cellular Immunity

by John T. Keane and Avery D. Posey, Jr.

Cells 2021, 10(12), 3356; https://doi.org/10.3390/cells10123356 - 30 Nov 2021

Cited by 6 | Viewed by 2755

Abstract

T-cell therapies have made significant improvements in cancer treatment over the last decade. One cellular therapy utilizing T-cells involves the use of a chimeric MHC-independent antigen-recognition receptor, typically referred to as a chimeric antigen receptor (CAR). CAR molecules, while mostly limited to the [...] Read more.

T-cell therapies have made significant improvements in cancer treatment over the last decade. One cellular therapy utilizing T-cells involves the use of a chimeric MHC-independent antigen-recognition receptor, typically referred to as a chimeric antigen receptor (CAR). CAR molecules, while mostly limited to the recognition of antigens on the surface of tumor cells, can also be utilized to exploit the diverse repertoire of macromolecules targetable by antibodies, which are incorporated into the CAR design. Leaning into this expansion of target macromolecules will enhance the diversity of antigens T-cells can target and may improve the tumor-specificity of CAR T-cell therapy. This review explores the types of macromolecules targetable by T-cells through endogenous and synthetic antigen-specific receptors. Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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20 pages, 9571 KiB

Open AccessFeature PaperReview

Evolution of CD8⁺ T Cell Receptor (TCR) Engineered Therapies for the Treatment of Cancer

by Yimo Sun, Fenge Li, Heather Sonnemann, Kyle R. Jackson, Amjad H. Talukder, Arjun S. Katailiha and Gregory Lizee

Cells 2021, 10(9), 2379; https://doi.org/10.3390/cells10092379 - 10 Sep 2021

Cited by 23 | Viewed by 14610

Abstract

Engineered T cell receptor T (TCR-T) cell therapy has facilitated the generation of increasingly reliable tumor antigen-specific adaptable cellular products for the treatment of human cancer. TCR-T cell therapies were initially focused on targeting shared tumor-associated peptide targets, including melanoma differentiation and cancer-testis [...] Read more.

Engineered T cell receptor T (TCR-T) cell therapy has facilitated the generation of increasingly reliable tumor antigen-specific adaptable cellular products for the treatment of human cancer. TCR-T cell therapies were initially focused on targeting shared tumor-associated peptide targets, including melanoma differentiation and cancer-testis antigens. With recent technological developments, it has become feasible to target neoantigens derived from tumor somatic mutations, which represents a highly personalized therapy, since most neoantigens are patient-specific and are rarely shared between patients. TCR-T therapies have been tested for clinical efficacy in treating solid tumors in many preclinical studies and clinical trials all over the world. However, the efficacy of TCR-T therapy for the treatment of solid tumors has been limited by a number of factors, including low TCR avidity, off-target toxicities, and target antigen loss leading to tumor escape. In this review, we discuss the process of deriving tumor antigen-specific TCRs, including the identification of appropriate tumor antigen targets, expansion of antigen-specific T cells, and TCR cloning and validation, including techniques and tools for TCR-T cell vector construction and expression. We highlight the achievements of recent clinical trials of engineered TCR-T cell therapies and discuss the current challenges and potential solutions for improving their safety and efficacy, insights that may help guide future TCR-T studies in cancer. Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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15 pages, 1253 KiB

Open AccessReview

Targeting Natural Killer T Cells in Solid Malignancies

by Zewde Ingram, Shriya Madan, Jenoy Merchant, Zakiya Carter, Zen Gordon, Gregory Carey and Tonya J. Webb

Cells 2021, 10(6), 1329; https://doi.org/10.3390/cells10061329 - 27 May 2021

Cited by 16 | Viewed by 4093

Abstract

Natural killer T (NKT) cells are a unique subset of lymphocytes that recognize lipid antigens in the context of the non-classical class I MHC molecule, CD1d, and serve as a link between the innate and adaptive immune system through their expeditious release of [...] Read more.

Natural killer T (NKT) cells are a unique subset of lymphocytes that recognize lipid antigens in the context of the non-classical class I MHC molecule, CD1d, and serve as a link between the innate and adaptive immune system through their expeditious release of cytokines. Whereas NKT have well-established roles in mitigating a number of human diseases, herein, we focus on their role in cancer. NKT cells have been shown to directly and indirectly mediate anti-tumor immunity and manipulating their effector functions can have therapeutic significances in treatment of cancer. In this review, we highlight several therapeutic strategies that have been used to harness the effector functions of NKT cells to target different types of solid tumors. We also discuss several barriers to the successful utilization of NKT cells and summarize effective strategies being developed to harness the unique strengths of this potent population of T cells. Collectively, studies investigating the therapeutic potential of NKT cells serve not only to advance our understanding of this powerful immune cell subset, but also pave the way for future treatments focused on the modulation of NKT cell responses to enhance cancer immunotherapy. Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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17 pages, 1212 KiB

Open AccessReview

Mast Cells: A New Frontier for Cancer Immunotherapy

by Jake N. Lichterman and Sangeetha M. Reddy

Cells 2021, 10(6), 1270; https://doi.org/10.3390/cells10061270 - 21 May 2021

Cited by 56 | Viewed by 7859

Abstract

Mast cells are unique tissue-resident immune cells of the myeloid lineage that have long been implicated in the pathogenesis of allergic and autoimmune disorders. More recently, mast cells have been recognized as key orchestrators of anti-tumor immunity, modulators of the cancer stroma, and [...] Read more.

Mast cells are unique tissue-resident immune cells of the myeloid lineage that have long been implicated in the pathogenesis of allergic and autoimmune disorders. More recently, mast cells have been recognized as key orchestrators of anti-tumor immunity, modulators of the cancer stroma, and have also been implicated in cancer cell intrinsic properties. As such, mast cells are an underrecognized but very promising target for cancer immunotherapy. In this review, we discuss the role of mast cells in shaping cancer and its microenvironment, the interaction between mast cells and cancer therapies, and strategies to target mast cells to improve cancer outcomes. Specifically, we address (1) decreasing cell numbers through c-KIT inhibition, (2) modulating mast cell activation and phenotype (through mast cell stabilizers, FcεR1 signaling pathway activators/inhibitors, antibodies targeting inhibitory receptors and ligands, toll like receptor agonists), and (3) altering secreted mast cell mediators and their downstream effects. Finally, we discuss the importance of translational research using patient samples to advance the field of mast cell targeting to optimally improve patient outcomes. As we aim to expand the successes of existing cancer immunotherapies, focused clinical and translational studies targeting mast cells in different cancer contexts are now warranted. Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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31 pages, 1745 KiB

Open AccessReview

Tissue-Resident and Recruited Macrophages in Primary Tumor and Metastatic Microenvironments: Potential Targets in Cancer Therapy

by Tiziana Cotechini, Aline Atallah and Arielle Grossman

Cells 2021, 10(4), 960; https://doi.org/10.3390/cells10040960 - 20 Apr 2021

Cited by 31 | Viewed by 6305

Abstract

Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast [...] Read more.

Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis. Both recruited and tissue-resident macrophage populations contribute to tumor growth and metastasis and are important mediators of resistance to chemotherapy, radiation therapy, and immune checkpoint blockade. Thus, targeting various macrophage populations and their tumor-promoting phenotypes holds therapeutic promise. Here, we discuss various macrophage populations as regulators of tumor progression, immunity, and immunotherapy. We provide an overview of macrophage targeting strategies, including therapeutics designed to induce macrophage depletion, impair recruitment, and induce repolarization. We also provide a perspective on the therapeutic potential for macrophage-specific acquisition of trained immunity as an anti-cancer agent and discuss the therapeutic potential of exploiting macrophages and their traits to reduce tumor burden. Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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17 pages, 2039 KiB

Open AccessReview

Adoptive T Cell Therapy for Solid Tumors: Pathway to Personalized Standard of Care

by Shuyang S. Qin, Alexa D. Melucci, Alexander C. Chacon and Peter A. Prieto

Cells 2021, 10(4), 808; https://doi.org/10.3390/cells10040808 - 5 Apr 2021

Cited by 20 | Viewed by 6286

Abstract

Adoptive cell therapy (ACT) with tumor-infiltrating T cells (TILs) has emerged as a promising therapy for the treatment of unresectable or metastatic solid tumors. One challenge to finding a universal anticancer treatment is the heterogeneity present between different tumors as a result of [...] Read more.

Adoptive cell therapy (ACT) with tumor-infiltrating T cells (TILs) has emerged as a promising therapy for the treatment of unresectable or metastatic solid tumors. One challenge to finding a universal anticancer treatment is the heterogeneity present between different tumors as a result of genetic instability associated with tumorigenesis. As the epitome of personalized medicine, TIL-ACT bypasses the issue of intertumoral heterogeneity by utilizing the patient’s existing antitumor immune response. Despite being one of the few therapies capable of inducing durable, complete tumor regression, many patients fail to respond. Recent research has focused on increasing therapeutic efficacy by refining various aspects of the TIL protocol, which includes the isolation, ex vivo expansion, and subsequent infusion of tumor specific lymphocytes. This review will explore how the therapy has evolved with time by highlighting various resistance mechanisms to TIL therapy and the novel strategies to overcome them. Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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