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15 pages, 5863 KiB

Open AccessArticle

Tumor-Localized Administration of α-GalCer to Recruit Invariant Natural Killer T Cells and Enhance Their Antitumor Activity against Solid Tumors

by Yan-Ruide Li, Yang Zhou, Matthew Wilson, Adam Kramer, Ryan Hon, Yichen Zhu, Ying Fang and Lili Yang

Int. J. Mol. Sci. 2022, 23(14), 7547; https://doi.org/10.3390/ijms23147547 - 07 Jul 2022

Cited by 7 | Viewed by 2790

Abstract

Invariant natural killer T (iNKT) cells have the capacity to mount potent anti-tumor reactivity and have therefore become a focus in the development of cell-based immunotherapy. iNKT cells attack tumor cells using multiple mechanisms with a high efficacy; however, their clinical application has [...] Read more.

Invariant natural killer T (iNKT) cells have the capacity to mount potent anti-tumor reactivity and have therefore become a focus in the development of cell-based immunotherapy. iNKT cells attack tumor cells using multiple mechanisms with a high efficacy; however, their clinical application has been limited because of their low numbers in cancer patients and difficulties in infiltrating solid tumors. In this study, we aimed to overcome these critical limitations by using α-GalCer, a synthetic glycolipid ligand specifically activating iNKT cells, to recruit iNKT to solid tumors. By adoptively transferring human iNKT cells into tumor-bearing humanized NSG mice and administering a single dose of tumor-localized α-GalCer, we demonstrated the rapid recruitment of human iNKT cells into solid tumors in as little as one day and a significantly enhanced tumor killing ability. Using firefly luciferase-labeled iNKT cells, we monitored the tissue biodistribution and pharmacokinetics/pharmacodynamics (PK/PD) of human iNKT cells in tumor-bearing NSG mice. Collectively, these preclinical studies demonstrate the promise of an αGC-driven iNKT cell-based immunotherapy to target solid tumors with higher efficacy and precision. Full article

(This article belongs to the Special Issue Immunological Approaches in Tumor Therapy)

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19 pages, 3372 KiB

Open AccessArticle

Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy

by Margherita Passariello, Asami Yoshioka, Kota Takahashi, Shu-ichi Hashimoto, Rosa Rapuano Lembo, Lorenzo Manna, Koji Nakamura and Claudia De Lorenzo

Int. J. Mol. Sci. 2022, 23(7), 3466; https://doi.org/10.3390/ijms23073466 - 23 Mar 2022

Cited by 7 | Viewed by 2652

Abstract

Cancer immunotherapy has already shown significant improvements by combining different antibodies specific for distinct immune checkpoints, such as Ipilimumab and Nivolumab. Here, we tested combinatorial treatments of immunomodulatory antibodies, previously generated in our laboratory, for their effects on hPBMC activation, either upon stimulation [...] Read more.

Cancer immunotherapy has already shown significant improvements by combining different antibodies specific for distinct immune checkpoints, such as Ipilimumab and Nivolumab. Here, we tested combinatorial treatments of immunomodulatory antibodies, previously generated in our laboratory, for their effects on hPBMC activation, either upon stimulation with SEB or in co-cultures with tumor cells by cytokine secretion assays. We found that some of them showed additive or synergistic effects, and on the basis of these observations, we constructed, for the first time, four novel bispecific tribodies (TR), made up of a Fab derived from one anti-IC mAb and two scFvs derived from another mAb targeting a different IC. All four TRs cotargeting either programmed cell death protein 1 (PD-1) and Lymphocyte Activating 3 (LAG-3) or programmed death-ligand 1 (PD-L1) and LAG-3 retained binding affinity for their targets and the antagonistic effects of their parental mAbs, but some of them also showed an increased ability to induce lymphocyte activation and increased in vitro cytotoxicity against tumor cells compared to parental antibodies used either alone or in combinatorial treatments. Furthermore, none of the tribodies showed significant increased cytotoxicity on human cardiomyocytes. Considering that the tribody format reduces production costs (as only one construct provides the inhibitory effects of two antibodies), has an intermediate molecular size (100 kDa) which is well suited for both tumor penetration and an acceptable half-life, we think that these novel immunomodulatory TRBs have the potential to become precious tools for therapeutic applications, particularly in monotherapy-resistant cancer patients. Full article

(This article belongs to the Special Issue Immunological Approaches in Tumor Therapy)

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19 pages, 2639 KiB

Open AccessArticle

Combined Blockade of TIGIT and CD39 or A2AR Enhances NK-92 Cell-Mediated Cytotoxicity in AML

by Franziska Brauneck, Elisa Seubert, Jasmin Wellbrock, Julian Schulze zur Wiesch, Yinghui Duan, Tim Magnus, Carsten Bokemeyer, Friedrich Koch-Nolte, Stephan Menzel and Walter Fiedler

Int. J. Mol. Sci. 2021, 22(23), 12919; https://doi.org/10.3390/ijms222312919 - 29 Nov 2021

Cited by 29 | Viewed by 3997

Abstract

This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and peripheral blood cells from acute myeloid leukemia (AML) patients and healthy donors (HDs). Our data show that CD56^dimCD16⁻ and CD56^brightCD16⁻ NK cells [...] Read more.

This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and peripheral blood cells from acute myeloid leukemia (AML) patients and healthy donors (HDs). Our data show that CD56^dimCD16⁻ and CD56^brightCD16⁻ NK cells represent the predominant NK cell subpopulations in AML, while the CD56^dimCD16⁺ NK cells are significantly reduced compared to HDs. Moreover, TIGIT⁺ and PVRIG⁺ cells cluster on the CD56^dimCD16⁺ subset whereas CD39⁺ and CD38⁺ cells do so on CD56^brightCD16⁻ NK cells in AML. Furthermore, functional effects of (co-)blockade of TIGIT and CD39 or A2AR on NK cell functionality were analyzed. These experiments revealed that the single blockade of the TIGIT receptor results in an increased NK-92 cell-mediated killing of AML cells in vitro. Combined targeting of CD39 or A2AR significantly augments the anti-TIGIT-mediated lysis of AML cells. Our data indicate that distinct NK cell subsets in AML exhibit different immunosuppressive patterns (via the TIGIT/PVRIG receptors and the purinergic pathway). In summary, we conclude that TIGIT, CD39, and A2AR constitute relevant inhibitory checkpoints of NK cells in AML patients. A combinatorial blockade synergistically strengthens NK-92 cell-mediated cytotoxicity. As inhibitors of TIGIT, CD39, and A2AR are clinically available, studies on their combined use could be conducted in the near future. Full article

(This article belongs to the Special Issue Immunological Approaches in Tumor Therapy)

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17 pages, 2953 KiB

Open AccessArticle

Folate Receptor Beta as a Direct and Indirect Target for Antibody-Based Cancer Immunotherapy

by Allison G. Roy, J. Michael Robinson, Prannda Sharma, Alba Rodriguez-Garcia, Mathilde A. Poussin, Cheryl Nickerson-Nutter and Daniel J. Powell, Jr.

Int. J. Mol. Sci. 2021, 22(11), 5572; https://doi.org/10.3390/ijms22115572 - 25 May 2021

Cited by 11 | Viewed by 3187

Abstract

Folate receptor beta (FRβ) is a folate binding receptor expressed on myeloid lineage hematopoietic cells. FRβ is commonly expressed at high levels on malignant blasts in patients with acute myeloid leukemia (AML), as well as on M2 polarized tumor-associated macrophages (TAMs) in the [...] Read more.

Folate receptor beta (FRβ) is a folate binding receptor expressed on myeloid lineage hematopoietic cells. FRβ is commonly expressed at high levels on malignant blasts in patients with acute myeloid leukemia (AML), as well as on M2 polarized tumor-associated macrophages (TAMs) in the tumor microenvironment of many solid tumors. Therefore, FRβ is a potential target for both direct and indirect cancer therapy. We demonstrate that FRβ is expressed in both AML cell lines and patient-derived AML samples and that a high-affinity monoclonal antibody against FRβ (m909) has the ability to cause dose- and expression-dependent ADCC against these cells in vitro. Importantly, we find that administration of m909 has a significant impact on tumor growth in a humanized mouse model of AML. Surprisingly, m909 functions in vivo with and without the infusion of human NK cells as mediators of ADCC, suggesting potential involvement of mouse macrophages as effector cells. We also found that TAMs from primary ovarian ascites samples expressed appreciable levels of FRβ and that m909 has the ability to cause ADCC in these samples. These results indicate that the targeting of FRβ using m909 has the potential to limit the outgrowth of AML in vitro and in vivo. Additionally, m909 causes cytotoxicity to TAMs in the tumor microenvironment of ovarian cancer warranting further investigation of m909 and its derivatives as therapeutic agents in patients with FRβ-expressing cancers. Full article

(This article belongs to the Special Issue Immunological Approaches in Tumor Therapy)

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20 pages, 11622 KiB

Open AccessArticle

Infiltration of Immune Competent Cells into Primary Tumors and Their Surrounding Connective Tissues in Xenograft and Syngeneic Mouse Models

by Marlon Metzen, Michael Bruns, Wolfgang Deppert and Udo Schumacher

Int. J. Mol. Sci. 2021, 22(8), 4213; https://doi.org/10.3390/ijms22084213 - 19 Apr 2021

Cited by 3 | Viewed by 2258

Abstract

To fight cancer more efficiently with cell-based immunotherapy, more information about the cells of the immune system and their interaction with cancer cells in vivo is needed. Therefore paraffin wax embedded primary breast cancers from the syngeneic mouse WAP-T model and from xenografted [...] Read more.

To fight cancer more efficiently with cell-based immunotherapy, more information about the cells of the immune system and their interaction with cancer cells in vivo is needed. Therefore paraffin wax embedded primary breast cancers from the syngeneic mouse WAP-T model and from xenografted tumors of breast, colon, melanoma, ovarian, neuroblastoma, pancreatic, prostate, and small cell lung cancer were investigated for the infiltration of immunocompetent cells by immunohistochemistry using antibodies against leukocyte markers. The following markers were used: CD45 as a pan-leukocyte marker, BSA-I as a dendritic cell marker, CD11b as an NK cell marker, and CD68 as a marker for macrophages. The labeled immune cells were attributed to the following locations: adjacent adipose tissue, tumor capsule, intra-tumoral septae, and cancer cells directly. In xenograft tumors, the highest score of CD45 and CD11b positive, NK, and dendritic cells were found in the adjacent adipose tissue, followed by lesser infiltration directly located at the cancer cells themselves. The detected numbers of CD45 positive cells differed between the tumor entities: few infiltrating cells in breast cancer, small cell lung cancer, neuroblastoma, a moderate infiltration in colon cancer, melanoma and ovarian cancer, strongest infiltration in prostate and pancreatic cancer. In the syngeneic tumors, the highest score of CD45 and CD11b positive, NK and dendritic cells were observed in the tumor capsule, followed by a lesser infiltration of the cancer tissue. Our findings argue for paying more attention to investigate how immune-competent cells can reach the tumor cells directly. Full article

(This article belongs to the Special Issue Immunological Approaches in Tumor Therapy)

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Review

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20 pages, 1187 KiB

Open AccessReview

Interleukin 15 in Cell-Based Cancer Immunotherapy

by Yang Zhou, Tiffany Husman, Xinjian Cen, Tasha Tsao, James Brown, Aarushi Bajpai, Miao Li, Kuangyi Zhou and Lili Yang

Int. J. Mol. Sci. 2022, 23(13), 7311; https://doi.org/10.3390/ijms23137311 - 30 Jun 2022

Cited by 22 | Viewed by 7366

Abstract

Cell-based cancer immunotherapy, such as chimeric antigen receptor (CAR) engineered T and natural killer (NK) cell therapies, has become a revolutionary new pillar in cancer treatment. Interleukin 15 (IL-15), a potent immunostimulatory cytokine that potentiates T and NK cell immune responses, has demonstrated [...] Read more.

Cell-based cancer immunotherapy, such as chimeric antigen receptor (CAR) engineered T and natural killer (NK) cell therapies, has become a revolutionary new pillar in cancer treatment. Interleukin 15 (IL-15), a potent immunostimulatory cytokine that potentiates T and NK cell immune responses, has demonstrated the reliability and potency to potentially improve the therapeutic efficacy of current cell therapy. Structurally similar to interleukin 2 (IL-2), IL-15 supports the persistence of CD8⁺ memory T cells while inhibiting IL-2-induced T cell death that better maintains long-term anti-tumor immunity. In this review, we describe the biology of IL-15, studies on administrating IL-15 and/or its derivatives as immunotherapeutic agents, and IL-15-armored immune cells in adoptive cell therapy. We also discuss the advantages and challenges of incorporating IL-15 in cell-based immunotherapy and provide directions for future investigation. Full article

(This article belongs to the Special Issue Immunological Approaches in Tumor Therapy)

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20 pages, 2451 KiB

Open AccessReview

Vaccines for Non-Viral Cancer Prevention

by Cristina Bayó, Gerhard Jung, Marta Español-Rego, Francesc Balaguer and Daniel Benitez-Ribas

Int. J. Mol. Sci. 2021, 22(20), 10900; https://doi.org/10.3390/ijms222010900 - 09 Oct 2021

Cited by 6 | Viewed by 2479

Abstract

Cancer vaccines are a type of immune therapy that seeks to modulate the host’s immune system to induce durable and protective immune responses against cancer-related antigens. The little clinical success of therapeutic cancer vaccines is generally attributed to the immunosuppressive tumor microenvironment at [...] Read more.

Cancer vaccines are a type of immune therapy that seeks to modulate the host’s immune system to induce durable and protective immune responses against cancer-related antigens. The little clinical success of therapeutic cancer vaccines is generally attributed to the immunosuppressive tumor microenvironment at late-stage diseases. The administration of cancer-preventive vaccination at early stages, such as pre-malignant lesions or even in healthy individuals at high cancer risk could increase clinical efficacy by potentiating immune surveillance and pre-existing specific immune responses, thus eliminating de novo appearing lesions or maintaining equilibrium. Indeed, research focus has begun to shift to these approaches and some of them are yielding encouraging outcomes. Full article

(This article belongs to the Special Issue Immunological Approaches in Tumor Therapy)

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19 pages, 1234 KiB

Open AccessReview

Combining Cancer Vaccines with Immunotherapy: Establishing a New Immunological Approach

by Chang-Gon Kim, Yun-Beom Sang, Ji-Hyun Lee and Hong-Jae Chon

Int. J. Mol. Sci. 2021, 22(15), 8035; https://doi.org/10.3390/ijms22158035 - 27 Jul 2021

Cited by 29 | Viewed by 5111

Abstract

Therapeutic cancer vaccines have become increasingly qualified for use in personalized cancer immunotherapy. A deeper understanding of tumor immunology and novel antigen delivery technologies has assisted in optimizing vaccine design. Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells, thereby [...] Read more.

Therapeutic cancer vaccines have become increasingly qualified for use in personalized cancer immunotherapy. A deeper understanding of tumor immunology and novel antigen delivery technologies has assisted in optimizing vaccine design. Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells, thereby leading to effective tumor regression and minimizing non-specific or adverse events. However, due to several resistance mechanisms, significant challenges remain to be solved in order to achieve these goals. In this review, we describe our current understanding with respect to the use of the antigen repertoire in vaccine platform development. We also summarize various intrinsic and extrinsic resistance mechanisms behind the failure of cancer vaccine development in the past. Finally, we suggest a strategy that combines immune checkpoint inhibitors to enhance the efficacy of cancer vaccines. Full article

(This article belongs to the Special Issue Immunological Approaches in Tumor Therapy)

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