Switching on the macrophage-mediated suppressor mechanism by tumor cells to evade host immune surveillance.

Abstract [Purpose and background] Adult T-cell leukemia/lymphoma (ATLL) caused by HTLV-I virus infection is one of the most aggressive lymphoid malignancies with short prognosis, of which best-reported median survival by combined chemotherapy is 13 months. Even at the disease onset, opportunistic infections are frequently complicated. Thus, host immune system both against tumor and infection is considered to be severely impaired in ATLL patients. However precise mechanism underlying that immunodeficiency still remains undetermined. Recently the lines of evidence that co-inhibitory molecules;programmed death-1/programmed death-1 ligand (PD-1/PD-L1) pathway in T-cell activation seems to play a crucial role in tumor escape from host immune surveillance system have been accumulated. In this study, we investigated the expression of PD-L1 on ATLL cells (CD4+/CD25+), and as their counterparts, CD4+ lymphocytes from HTLV-I asymptomatic carriers (ACs) to define their clinical significance. [Patients and Methods] Peripheral blood CD4+ lymphocytes from 11 ATLL patients (9; untreated, 2; progressive state), 12 ACs and 2 healthy donors (HDs) were investigated for PD-L1 expression. We simultaneously measured co-inhibitory receptor, PD-1, expression on CD8+ HTLV-I Tax-specific cytotoxic lymphocytes (anti-Tax CTLs), as a marker of immunity against HTLV-I. [Results] PD-L1 expression was detected on CD4+ lymphocytes in 3 of the 11 ATLL patients and 2 of them were in progressive state. In contrast, none of the ACs or HDs expressed PD-L1 on CD4+ lymphocytes, while those cultured with IL-2 for 48hs transiently expressed PD-L1. Anti-Tax CTLs were detected in 6 of the 11 ATLL patients and all of those CTL expressed PD-1 simultaneously. Anti-Tax CTLs were not detected in the 2 cases in progressive state. Anti-Tax CTLs were detected in 9 of 12 ACs, and PD-1 also co-expressed on those CTLs. [Conclusions] CD4+ ATLL cells in progressive state expressed cell surface PD-L1, but not in untreated patients or ACs. This is a striking finding that exclusively aggressive form of ATLL tumor cells expressed cell surface PD-L1, which renders tumor cells to evade from host immune surveillance systems. Nonetheless large scale studies are needed to confirm these findings. In addition, Interestingly, co-inhibitory molecule PD-1 expressed on anti-Tax CTLs in not only ATLL patients but also ACs. Because PD-1 expression of CTL means “exhausted”, our observation suggests that anti-HTLV-I virus immunity is already exhausted both ATLL patients and ACs. Further experiments are warranted to define the significance of the correlation between PD-L1 on ATLL cells and PD-1 on anti-HTLV-I CTL in ATLL patients and ACs.

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Recent Advances to Augment NK Cell Cancer Immunotherapy Using Nanoparticles

Pharmaceutics ◽

10.3390/pharmaceutics13040525 ◽

2021 ◽

Vol 13 (4) ◽

pp. 525

Author(s):

Kwang-Soo Kim ◽

Dong-Hwan Kim ◽

Dong-Hyun Kim

Keyword(s):

Clinical Trials ◽

Nk Cells ◽

Cancer Immunotherapy ◽

Tumor Cells ◽

Therapeutic Efficacy ◽

Nk Cell ◽

Cell Cancer ◽

Immune Surveillance ◽

Cytolytic Activity ◽

Contact Frequency

Among various immunotherapies, natural killer (NK) cell cancer immunotherapy using adoptive transfer of NK cells takes a unique position by targeting tumor cells that evade the host immune surveillance. As the first-line innate effector cell, it has been revealed that NK cells have distinct mechanisms to both eliminate cancer cells directly and amplify the anticancer immune system. Over the last 40 years, NK cell cancer immunotherapy has shown encouraging reports in pre-clinic and clinic settings. In total, 288 clinical trials are investigating various NK cell immunotherapies to treat hematologic and solid malignancies in 2021. However, the clinical outcomes are unsatisfying, with remained challenges. The major limitation is attributed to the immune-suppressive tumor microenvironment (TME), low activity of NK cells, inadequate homing of NK cells, and limited contact frequency of NK cells with tumor cells. Innovative strategies to promote the cytolytic activity, durable persistence, activation, and tumor-infiltration of NK cells are required to advance NK cell cancer immunotherapy. As maturing nanotechnology and nanomedicine for clinical applications, there is a greater opportunity to augment NK cell therapeutic efficacy for the treatment of cancers. Active molecules/cytokine delivery, imaging, and physicochemical properties of nanoparticles are well equipped to overcome the challenges of NK cell cancer immunotherapy. Here, we discuss recent clinical trials of NK cell cancer immunotherapy, NK cell cancer immunotherapy challenges, and advances of nanoparticle-mediated NK cell therapeutic efficacy augmentation.

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The Impact of Interferon Gamma Receptor Expression on the Mechanism of Escape From Host Immune Surveillance in Hepatocellular Carcinoma

Hepatology ◽

10.1053/jhep.2000.16470 ◽

2000 ◽

Vol 32 (3) ◽

pp. 491-500 ◽

Cited By ~ 34

Author(s):

Mitsuo Nagao ◽

Yoshiyuki Nakajima ◽

Hiromichi Kanehiro ◽

Michiyoshi Hisanaga ◽

Yukio Aomatsu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Interferon Gamma ◽

Immune Surveillance ◽

Receptor Expression ◽

Gamma Receptor ◽

The Impact ◽

Host Immune Surveillance

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A NONLINEAR DELAY MODEL DESCRIBING THE GROWTH OF TUMOR CELLS UNDER IMMUNE SURVEILLANCE AGAINST CANCER AND ITS STABILITY ANALYSIS

International Journal of Biomathematics ◽

10.1142/s1793524512600170 ◽

2012 ◽

Vol 05 (03) ◽

pp. 1260017 ◽

Cited By ~ 2

Author(s):

LING CHEN ◽

WANBIAO MA

Keyword(s):

Stability Analysis ◽

Hopf Bifurcation ◽

Periodic Solutions ◽

Tumor Cells ◽

Local Stability ◽

Immune Surveillance ◽

Delay Model ◽

Existence Of Periodic Solutions ◽

Growth Of Tumor ◽

Nonlinear Delay

In this paper, based on some biological meanings and a model which was proposed by Lefever and Garay (1978), a nonlinear delay model describing the growth of tumor cells under immune surveillance against cancer is given. Then, boundedness of the solutions, local stability of the equilibria and Hopf bifurcation of the model are discussed in details. The existence of periodic solutions explains the restrictive interactions between immune surveillance and the growth of the tumor cells.

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Inhibition of Indoleamine-2,3-dioxygenase (IDO) in Glioblastoma Cells by Oncolytic Herpes Simplex Virus

Advances in Virology ◽

10.1155/2012/815465 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Bonnie Reinhart ◽

Lucia Mazzacurati ◽

Adriana Forero ◽

Chang-Sook Hong ◽

Junichi Eguchi ◽

...

Keyword(s):

Tumor Cells ◽

Virus Replication ◽

Immune Escape ◽

Immune Surveillance ◽

Innate Immune ◽

Glioblastoma Cells ◽

Indoleamine 2,3 Dioxygenase ◽

Oncolytic Herpes Simplex Virus ◽

Hel Cells ◽

Simplex Virus

Successful oncolytic virus treatment of malignant glioblastoma multiforme depends on widespread tumor-specific lytic virus replication and escape from mitigating innate immune responses to infection. Here we characterize a new HSV vector, JD0G, that is deleted for ICP0 and the joint sequences separating the unique long and short elements of the viral genome. We observed that JD0G replication was enhanced in certain glioblastoma cell lines compared to HEL cells, suggesting that a vector backbone deleted for ICP0 may be useful for treatment of glioblastoma. The innate immune response to virus infection can potentially impede oncolytic vector replication in human tumors. Indoleamine-2,3-dioxygenase (IDO) is expressed in response to interferonγ(IFNγ) and has been linked to both antiviral functions and to the immune escape of tumor cells. We observed that IFNγtreatment of human glioblastoma cells induced the expression of IDO and that this expression was quelled by infection with both wild-type and JD0G viruses. The role of IDO in inhibiting virus replication and the connection of this protein to the escape of tumor cells from immune surveillance suggest that IDO downregulation by HSV infection may enhance the oncolytic activity of vectors such as JD0G.

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Roles of Extracellular HSPs as Biomarkers in Immune Surveillance and Immune Evasion

International Journal of Molecular Sciences ◽

10.3390/ijms20184588 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4588 ◽

Cited By ~ 23

Author(s):

Eman A. Taha ◽

Kisho Ono ◽

Takanori Eguchi

Keyword(s):

Heat Shock ◽

Tumor Cells ◽

Cancer Progression ◽

Immune Evasion ◽

Checkpoint Inhibitors ◽

Membrane Surface ◽

Immune Surveillance ◽

Heat Shock Factor 1 ◽

Heterochromatin Protein 1 ◽

Liquid Biopsies

Extracellular heat shock proteins (ex-HSPs) have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, also known as alarmins. Such ex-HSPs include HSP90 (α, β, Gp96, Trap1), HSP70, and large and small HSPs. Production of HSPs is coordinately induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), while matrix metalloproteinase 3 (MMP-3) and heterochromatin protein 1 are novel inducers of HSPs. Oncosomes released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP) by which immune evasion can be established. The concepts of RASP are: (i) releases of ex-HSP and HSP-rich oncosomes are essential in RASP, by which molecular co-transfer of HSPs with oncogenic factors to recipient cells can promote cancer progression and resistance against stresses such as hypoxia, radiation, drugs, and immune systems; (ii) RASP of tumor cells can eject anticancer drugs, targeted therapeutics, and immune checkpoint inhibitors with oncosomes; (iii) cytotoxic lipids can be also released from tumor cells as RASP. ex-HSP and membrane-surface HSP (mHSP) play immunostimulatory roles recognized by CD91+ scavenger receptor expressed by endothelial cells-1 (SREC-1)+ Toll-like receptors (TLRs)+ antigen-presenting cells, leading to antigen cross-presentation and T cell cross-priming, as well as by CD94+ natural killer cells, leading to tumor cytolysis. On the other hand, ex-HSP/CD91 signaling in cancer cells promotes cancer progression. HSPs in body fluids are potential biomarkers detectable by liquid biopsies in cancers and tissue-damaged diseases. HSP-based vaccines, inhibitors, and RNAi therapeutics are also reviewed.

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Biochemical mechanisms implemented by human acute myeloid leukemia cells to suppress host immune surveillance

Cellular and Molecular Immunology ◽

10.1038/s41423-018-0047-6 ◽

2018 ◽

Vol 15 (11) ◽

pp. 989-991 ◽

Cited By ~ 5

Author(s):

Inna M. Yasinska ◽

Isabel Gonçalves Silva ◽

Svetlana Sakhnevych ◽

Bernhard F. Gibbs ◽

Ulrike Raap ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Immune Surveillance ◽

Leukemia Cells ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid Leukemia Cells ◽

Biochemical Mechanisms ◽

Host Immune Surveillance ◽

Acute Myeloid

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NK Cell Interaction With Platelets and Myeloid Cells in the Tumor Milieu

Frontiers in Immunology ◽

10.3389/fimmu.2020.608849 ◽

2020 ◽

Vol 11 ◽

Author(s):

Stefanie Maurer ◽

Lucas Ferrari de Andrade

Keyword(s):

Nk Cells ◽

Tumor Cells ◽

Nk Cell ◽

Germ Line ◽

Immune Surveillance ◽

Myeloid Cells ◽

Cell Interaction ◽

Underlying Mechanisms ◽

Antigen Presenting ◽

Surveillance Mechanism

Natural killer (NK) cells recognize and kill tumor cells via germ-line encoded receptors and polarized degranulation of cytotoxic molecules, respectively. As such, NK cells help to inhibit the development of cancers. The activating receptor NKG2D induces NK cell-mediated killing of metastasizing tumor cells by recognition of the stress-induced ligands MICA, MICB, and ULBP1-6. However, platelets enable escape from this immune surveillance mechanism by obstructing the interactions between NK cells and tumor cells or by cleaving the stress-induced ligands. It is also being increasingly appreciated that NK cells play additional roles in cancer immunity, including chemokine-mediated recruitment of antigen presenting cells in the tumor microenvironment that is followed by generation of adaptive immunity. However, the NK cell interplays with dendritic cells, and macrophages are extremely complex and involve molecular interactions via NKG2D and cytokine receptors. Specifically, NKG2D-mediated chronic interaction between NK cells and tumor-infiltrating macrophages causes immune suppression by differentiating NK cells toward a dysfunctional state. Here we discuss the underlying mechanisms of NK cell control by platelets and myeloid cells with focus on NKG2D and its ligands, and provide a timely perspective on how to harness these pathways with novel immunotherapeutic approaches.

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Tumor PD-L1 Induction by Resveratrol/Piceatannol May Function as a Search, Enhance, and Engage (“SEE”) Signal to Facilitate the Elimination of “Cold, Non-Responsive” Low PD-L1-Expressing Tumors by PD-L1 Blockade

International Journal of Molecular Sciences ◽

10.3390/ijms20235969 ◽

2019 ◽

Vol 20 (23) ◽

pp. 5969 ◽

Cited By ~ 2

Author(s):

Tze-Chen Hsieh ◽

Joseph M. Wu

Keyword(s):

Cell Death ◽

Antitumor Activity ◽

Programmed Cell Death ◽

Selection Criteria ◽

Regulatory Protein ◽

Immune Surveillance ◽

Tumor Escape ◽

Free Response ◽

High Level ◽

Host Immune Surveillance

Programmed cell death ligand 1 (PD-L1) is an immune regulatory protein that facilitates tumor escape from host immune surveillance. In the clinic, tumors with high level of PD-L1 have been used to identify patients who might respond favorably to treatment by anti-PD-L1 antibodies (PD-L1 blockade, PLB). Typically, a progression-free response of 9–20% to PLB has been observed, the basis for the low success rate is largely unknown. Recently, we show upregulation of PD-L1 in cancer cells by ≥IC50 supra-pharmacological dose of grape polyphenol resveratrol and piceatannol, alone and combined. Herein, we summarize recent published studies on the regulation of tumor PD-L1 by flavonoids and grape polyphenols. We hypothesize that the induced tumor PD-L1 by resveratrol and/or piceatannol may serve as a Search, Enhance, and Engage (“SEE”) signal to sensitize and augment the recognition and detection of low PD-L1-expressing “cold, non-responsive” tumors. The “SEE” strategy enhances the “visibility” of previously unidentified tumor cells for targeting and eventual eradication by the host antitumor activity. This strategy expands the selection criteria for patients with improved sensitivity and potential responsiveness when used in combination with PLB. The modulation of tumor PD-L1 by flavonoids or polyphenols is proposed to improve the response to PLB in low PD-L1 tumors.

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Unique Pattern of Raf-1 Kinase Inhibitory Protein (RKIP) Expression in Multiple Myeloma (MM) Compared to Other Tumor Types: Overexpression of RKIP and a Phosphorylated RKIP Is Common in MM Tumor Cells.

Blood ◽

10.1182/blood.v110.11.4852.4852 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4852-4852

Author(s):

Stavroula Baritaki ◽

Sara Huerta-Yepez ◽

Kam Yeung ◽

Manuel Penichet ◽

Haiming Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Tumor Cell ◽

Signaling Pathways ◽

Tumor Cells ◽

Cell Lines ◽

Immune Surveillance ◽

Myeloma Cell ◽

Inhibitory Protein ◽

Multiple Myeloma Cell ◽

Survival Signaling

Abstract Objective and Rationale Raf-1 kinase inhibitory protein (RKIP) is a modulator of cell signaling and survival that functions as an endogenous inhibitor of multiple kinases, including kinases involved in the Raf/MEK/ERK and NF-κB pathways. RKIP has been identified as a metastasis suppressor gene and an immune surveillance cancer gene, since loss of RKIP protein expression has been associated with tumor progression, metastasis and escape from immune surveillance. Further, RKIP expression has been associated with prognostic significance in many cancers. Recently, we have demonstrated that induction of RKIP expression in tumors with low RKIP levels results in increased tumor cell sensitivity to immuno- or chemo-therapy via inhibition of the above pathways. However, multiple myeloma (MM) cells have been shown to express high RKIP levels compared to other tumors and still remain highly resistant to conventional cytotoxic therapies. These findings were unexpected and thus, it was plausible that the high level of RKIP expression was not functionally active. It has been reported that phosphorylation of RKIP at Ser-153 renders the cells inactive (Rosner et al., 2003, J Biol Chem 278:13061–8). Thus, we examined the expression and the phosphorylation status of the RKIP protein in several multiple myeloma cell lines and tissues and compared them with other cell lines with low RKIP expression. Hypothesis We hypothesized that MM tumor cells express high levels of the inactive phoshorylated RKIP protein which antagonizes the active non-phoshorylated RKIP form in the inhibition of the survival signaling pathways. Experimental Designs and Methods Multiple myeloma (IM-9, RPMI 8226, MM1S, U266 cell lines and fresh bone marrow samples from MM patients), PC-3 prostatic carcinoma and Ramos B-NHL cell lines were examined for total and phosphorylated RKIP expression by IHC and Western Blot analyses. The total RKIP protein was significantly elevated in multiple myeloma cell lines compared to the prostate and B-NHL lines. The predominant RKIP form in multiple myeloma tumors was the phosphorylated RKIP protein with high nuclear localization, as assessed by IHC, while the phosphorylated RKIP levels in the non-myeloma tumors were relatively low. It has been reported that the phosphorylation of RKIP is mediated by protein kinase C (Rosner et al., 2003, J Biol Chem 278:13061–8). Additional studies in multiple myeloma cell lines also revealed high expression of the zeta isoform of PKC (PKCζ), known to phosphorylate and inactivate RKIP. Conclusions and Implications The present findings demonstrate that the aberrant RKIP phosphorylation in multiple myeloma tumors may result in the inhibition of the suppressive effect of RKIP on tumor survival signaling pathways. We postulate that the high expression of RKIP may be due to inhibition of proteasome degradation. The present findings also suggest that screening of RKIP levels and RKIP phosphorylation status in MM may be useful as prognostic factors of tumor cell response to anti-tumor therapies.

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