Radiation therapy and the innate immune response: Clinical implications for immunotherapy approaches

Gómez, Valentí; Mustapha, Rami; Ng, Kenrick; Ng, Tony

doi:10.1111/bcp.14351

Cited by 21 publications

(16 citation statements)

References 111 publications

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“…Conventional therapies include the use of chemotherapy and radiation, but alternatives such as immunotherapy and the use of non-chemotherapeutic drugs are being researched. Conventional therapies are nonspecific as they kill cancer and healthy cells which could be very damaging to the individual as it can cause them to be in an immunosuppressive state whereby recurrent infections can occur [ 3 , 4 ]. Also, the use of conventional therapies creates the possibility of further inducing mutations in cancer and noncancer cells [ 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer

Buller

Mathew

2020

Cancers

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Natural killer (NK) cells play a pivotal role in the immune system, especially in the recognition and clearance of cancer cells and infected cells. Their effector function is controlled by a delicate balance between the activating and inhibitory signals. We have identified 2B4 (CD244, SLAMF4) and CS1 (CD319, SLAMF7) as NK cell receptors regulating NK cell cytotoxicity. Lectin-like transcript 1 (LLT1), a member of the C-type lectin-like domain family 2 (CLEC2D), induced IFN-γ production but did not directly regulate cytolytic activity. Interestingly, LLT1 expressed on other cells acts as a ligand for an NK cell inhibitory receptor NKRP1A (CD161) and inhibits NK cytolytic function. Extensive research has been done on novel therapies that target these receptors to increase the effector function of NK cells. The 2B4 receptor is involved in the rejection of melanoma cells in mice. Empliciti, an FDA-approved monoclonal antibody, explicitly targets the CS1 receptor and enhances the NK cell cytotoxicity against multiple myeloma cells. Our studies revealed that LLT1 is expressed on prostate cancer and triple-negative breast cancer cells and allows them to evade NK-cell-mediated killing. In this review, we describe NK cell receptors 2B4, CS1, and LLT1 and their potential in targeting cancer cells for NK-cell-mediated immunotherapy. New cancer immunotherapies like chimeric antigen receptor T (CAR-T) and NK (CAR-NK) cells are showing great promise in the treatment of cancer, and CAR cells specific to these receptors would be an attractive therapeutic option.

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Section: Introductionmentioning

confidence: 99%

Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer

Buller

Mathew

2020

Cancers

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“…Our data suggest that the combination of HDACi with NK cell-based immunotherapy, such as adoptive NK cell transfer may be beneficial for PDAC patients. Strategies including the combination of epigenetic approaches or radiation with immune therapy are under investigation [ 34 ].Thus, HDACi may be used to change the immunosuppressive TME and demask the tumor cells for immunotherapeutic approaches for example, with activated transferred NK cells. However, a better understanding and strategies to overcome the immunosuppressive TME diminishing NK cell activity for example, via targeting the oncoprotein SKI, is mandatory for further studies.…”

Section: Resultsmentioning

confidence: 99%

The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC

Ponath

Frech

Bittermann

et al. 2020

Cancers

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Drugs targeting epigenetic mechanisms such as histone deacetylase inhibitors (HDACi) suppress tumor growth. HDACi also induce the expression of ligands for the cytotoxicity receptor NKG2D rendering tumors more susceptible to natural killer (NK) cell-dependent killing. The major acetylases responsible for the expression of NKG2D ligands (NKG2D-L) are CBP and p300. The role of the oncogene and transcriptional repressor SKI, an essential part of an HDAC-recruiting co-repressor complex, which competes with CBP/p300 for binding to SMAD3 in TGFβ signaling, is unknown. Here we show that the siRNA-mediated downregulation of SKI in the pancreatic cancer cell lines Panc-1 and Patu8988t leads to an increased target cell killing by primary NK cells. However, the higher cytotoxicity of NK cells did not correlate with the induction of NKG2D-L. Of note, the expression of NKG2D-L and consequently NK cell-dependent killing could be induced upon LBH589 (LBH, panobinostat) or valproic acid (VPA) treatment irrespective of the SKI expression level but was significantly higher in pancreatic cancer cells upon genetic ablation of SKI. These data suggest that SKI represses the inducible expression of NKG2D-L. The combination of HDACi with NK cell-based immunotherapy is an attractive treatment option for pancreatic tumors, specifically for patients with high SKI protein levels.

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“…17 Mast cells and basophils, T cells, natural killer (NK) T cell subpopulations, and naive CD4þ T cells can produce IL-4, but Th2 cells are the most important producer of IL-4. 18 IL-4 has a wide range of biological activities and can enhance the killing function of specific and non-specific cells. Its role in the immune response in vivo is complex.…”

Section: Discussionmentioning

confidence: 99%

Exploring the optimal dose of low ionizing radiation to enhance immune function: a rabbit model

et al. 2021

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Primary liver cancer is one of the most common malignant tumors in China. Currently, immunotherapy for liver cancer is a research hotspot. Experimental studies and epidemiological investigations have confirmed the antineoplastic activity of low ionizing radiation. The aim of this study was to explore the optimal dose of low ionizing radiation to enhance immune function. Twenty-five New Zealand rabbits were randomly divided into five groups (n = 5 each): experimental group 1 (25 mGy), experimental group 2 (50 mGy), experimental group 3 (75 mGy), experimental group 4 (100 mGy), and the control group (0 mGy). VX-2 tumor tissue was injected into rabbits using a high-frequency B-ultrasound probe (3.5 MHz). Rabbits were irradiated, and on day 4 after irradiation, blood was collected from each rabbit. Blood chemistry, interleukin (IL)-4, interferon (IFN)-γ, immunoglobulin (Ig)G, and IgM levels were assessed. On day 15 after irradiation, macrophage phagocytic function was assessed. The rabbits were sacrificed, and the spleen was removed and weighed to calculate its spleen index. Each parameter was highest in the experimental group 3 (75 mGy). Thus, we suspect the optimal low ionizing radiation dose to improve immune function may be 75 mGy.

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Radiation therapy and the innate immune response: Clinical implications for immunotherapy approaches

Cited by 21 publications

References 111 publications

Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer

Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer

The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC

Exploring the optimal dose of low ionizing radiation to enhance immune function: a rabbit model

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