Targeting late-stage non-small cell lung cancer with a combination of DNT cellular therapy and PD-1 checkpoint blockade

Fang, Linan; Ly, Dalam; Wang, Sisi; Lee, Jong Bok; Kang, Hong‐Gyu; Xu, Hao; Yao, Jiang; Tsao, Ming‐Sound; Liu, Wei; Zhang, Li

doi:10.1186/s13046-019-1126-y

Cited by 44 publications

(55 citation statements)

References 49 publications

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“…48 DNTs have been previously reported to contribute to antimelanoma immunity. 49 In addition, this immunomodulatory effect is congruent with the reduced frequency of CD4 + T cell subpopulation as DNTs have been shown to suppress metabolic activation of CD4 + T cells (53) and could account for the CD4 + T cell reduction in this study. Nevertheless, the contribution of DNTs to antitumor immunity has only begun to be considered.…”

Section: Discussionsupporting

confidence: 70%

Immunomodulatory effects of renin–angiotensin system inhibitors on T lymphocytes in mice with colorectal liver metastases

Ardila

Walsh

Fifis

et al. 2020

J Immunother Cancer

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BackgroundIt is now recognized that many anticancer treatments positively modulate the antitumor immune response. Clinical and experimental studies have shown that inhibitors of the classical renin–angiotensin system (RAS) reduce tumor progression and are associated with better outcomes in patients with colorectal cancer. RAS components are expressed by most immune cells and adult hematopoietic cells, thus are potential targets for modulating tumor-infiltrating immune cells and can provide a mechanism of tumor control by the renin–angiotensin system inhibitors (RASi).AimTo investigate the effects of the RASi captopril on tumor T lymphocyte distribution in a mouse model of colorectal liver metastases.MethodsLiver metastases were established in a mouse model using an autologous colorectal cancer cell line. RASi (captopril 750 mg/kg) or carrier (saline) was administered to the mice daily via intraperitoneal injection, from day 1 post-tumor induction to endpoint (day 15 or 21 post-tumor induction). At the endpoint, tumor growth was determined, and lymphocyte infiltration and composition in the tumor and liver tissues were analyzed by flow cytometry and immunohistochemistry (IHC).ResultsCaptopril significantly decreased tumor viability and impaired metastatic growth. Analysis of infiltrating T cells into liver parenchyma and tumor tissues by IHC and flow cytometry showed that captopril significantly increased the infiltration of CD3+ T cells into both tissues at day 15 following tumor induction. Phenotypical analysis of CD45+ CD3+ T cells indicated that the major contributing phenotype to this influx is a CD4 and CD8 double-negative T cell (DNT) subtype, while CD4+ T cells decreased and CD8+ T cells remained unchanged. Captopril treatment also increased the expression of checkpoint receptor PD-1 on CD8+and DNT subsets .ConclusionCaptopril treatment modulates the immune response by increasing the infiltration and altering the phenotypical composition of T lymphocytes and may be a contributing mechanism for tumor control.

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Section: Discussionsupporting

confidence: 70%

Immunomodulatory effects of renin–angiotensin system inhibitors on T lymphocytes in mice with colorectal liver metastases

Ardila

Walsh

Fifis

et al. 2020

J Immunother Cancer

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“…Yao J et al [68] recently reported that IL-15 enhanced the killing effect of DNTs. Fang et al [69] showed that DNT tumor infiltration increased when combined with anti-PD-1 treatment, which enhanced DNT cell-mediated antitumor effects. Andrea Ponzetta et al [70] studied the role of DNTs in the tumor microenvironment and found that neutrophils can regulate the function of αβ+DNTs and that αβ+DNTs may have an essential role in antitumor immunity.…”

Section: Recent Progress In Dnt-based Immunotherapymentioning

confidence: 99%

“…DNTs combined with PD-1 inhibitor therapy achieve better efficacy. Fang et al [69] found that allogeneic DNTs from healthy donors killed lung cancer cells, and the combination of a PD-1 inhibitor increased the proportion of DNT infiltration in lung cancer tissues, thus inhibiting the growth of transplanted tumors in mice. These results show that adoptive infusion of DNTs may be a promising option for chemotherapy-resistant cancer, and the combination of DNTs with PD-1 inhibitor therapy may achieve better efficacy than either treatment alone.…”

Section: Applications Of Dntsmentioning

confidence: 99%

“…DNTs therapy significantly reduced lung tumor growth in patient-derived xenograft models but could not eradicate the full extent of the tumors; perhaps the lack of memory T cell formation in the immunodeficient mice was a key factor in this result. In addition, DNTs cannot continually maintain their alertness to tumor cells, and the tumor microenvironment limits the cytotoxicity of DNTs [69].…”

Section: Limitations Of Dntsmentioning

confidence: 99%

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DNT Cell-based Immunotherapy: Progress and Applications

Li¹,

Dong²,

Fan³

et al. 2020

J. Cancer

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Cancer immunotherapy has firmly established a dominant status in recent years. Adoptive cellular immunotherapy (ACI) is the main branch of immunotherapy. Recently, the immune effector cells of ACI, such as T cells, NK cells, and genetically engineered cells, have been used to achieve significant clinical benefits in the treatment of malignant tumors. However, the clinical applications have limitations, including toxicity, unexpectedly low efficiency, high costs and strict technical requirements. More exploration is needed to optimize ACI for cancer patients. CD3+CD4-CD8-double negative T cells (DNTs) have emerged as functional antitumor effector cells, according to the definition of adoptive immunotherapy. They constitute a kind of T cell subset that mediates nontumor antigen-restricted immunity and has important immune regulatory functions. Preclinical experiments showed that DNTs had a dual effect by killing tumor cells and inhibiting graft-versus-host disease. Notably, DNTs can be acquired from healthy donors and expanded in vitro; thus, allogeneic DNTs may be provided as "off-the-shelf" cellular products that can be readily available for direct clinical application. We review the progress and application of DNTs in immunotherapy. DNTs may provide some novel perspectives on cancer immunotherapy.

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“…To complement the general role of control and surveillance of malignant cells that the immune system play, the development of adoptive cellular therapy and checkpoint blockade has brought about a revolution in the landscape of cancer therapy and promises the potential in which oncologists can utilize a patient’s immune system to treat cancer. 185 , 261 – 263 Purinergic signaling axis has gained prominence as one of the mechanisms of tumor-mediated immunosuppressions, in which the purine nucleoside adenosine produced in the TME has the ability of potently suppressing NK cell function. 264 – 266 During this event, the production of extracellular adenosine is triggered by the mediation of the cell surface ectoenzymes CD38, CD39, and CD73, 267 – 269 and the development of therapeutic agents has focused on targeting these enzymes as responses.…”

Section: Study and Progress Of Adenosine In The Nk Cell Cancer Immunomentioning

confidence: 99%

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Cao

Wang

Jin

et al. 2020

Sig Transduct Target Ther

103

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Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

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Targeting late-stage non-small cell lung cancer with a combination of DNT cellular therapy and PD-1 checkpoint blockade

Cited by 44 publications

References 49 publications

Immunomodulatory effects of renin–angiotensin system inhibitors on T lymphocytes in mice with colorectal liver metastases

Immunomodulatory effects of renin–angiotensin system inhibitors on T lymphocytes in mice with colorectal liver metastases

DNT Cell-based Immunotherapy: Progress and Applications

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

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