Does Natural Killer Cell Deficiency (NKD) Increase the Risk of Cancer? NKD May Increase the Risk of Some Virus Induced Cancer

Moon, Won Young; Powis, Simon J.

doi:10.3389/fimmu.2019.01703

Cited by 34 publications

(30 citation statements)

References 33 publications

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“…As in our patient, low NK cell counts are found in up to 33% of post-transplant patients, and may further contribute to HPV susceptibility (22). Defects in NK cell function also increase risk of viral induced cancers (23,24). HPV infection, including genital warts, and poor NK killing in our patient put him at high risk for squamous cell carcinoma, highlighting the need for continued monitoring.…”

Section: Discussionmentioning

confidence: 51%

Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID

et al. 2020

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Introduction: Severe Combined Immunodeficiency (SCID) is a life-threatening immunodeficiency caused by several pathogenic genetic variants, and it is characterized by profound defects in T-cell numbers and immune function. First performed in the late 1960's, hematopoietic stem cell transplantation remains the standard treatment for most cases of SCID. There is a growing number of post-transplant SCID patients, and it is imperative to assess the long-term outcomes of these patients. We have reported here the longest follow-up of a post-transplant SCID patient who, to our knowledge, bears the first gamma chain (γc) variant to show intact IL-21 signaling. Case Presentation: The patient presented at 5 months of age with recurrent thrush and Pneumocystis jiroveci pneumonia. In 1971, at the age of 11 months, he received an unconditioned, matched, related donor transplant comprising whole, unprocessed bone marrow. He is now 48 years old without significant illness and has never required immunoglobulin replacement. He exhibits T-dependent vaccine responses. He does suffer from chronic warts and bacterial infections that have worsened in recent years. We confirmed a known pathogenic variant in the IL2RG gene showing a hemizygous variant NM_000206.2:c.675C>A, resulting in p.Ser225Arg. His chimerism studies revealed donor T cells, host B cells, host myeloid cells, and mixed NK cells. Lymphocyte enumeration revealed normal numbers and distribution of B cells. The host B cells carry the pathogenic variant in IL2RG, but, when stimulated with IL-21, they demonstrated intact, γc-dependent signaling. Conclusions: Even with host B cells, reconstitution with donor T cells can be sufficient to allow over four decades of survival when B-cell function is intact. Our case demonstrates that satisfactory B-cell function can arise as a consequence of both intact IL-21 signaling due to a hypomorphic γc variant, and close HLA matching with the donor to allow for effective T-cell help.

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Section: Discussionmentioning

confidence: 51%

Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID

et al. 2020

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“…I have also evaluated patients, upon request, who have had incidental laboratory findings have been obtained, and ultimately the only unifying theme I have been able to identify where NK cells are truly deficient is that of where patients have clinical susceptibility herpesviruses and some warts. I am not presently aware of enough signal to attribute cancer susceptibility to NKD but remain concerned and would refer the reader to a recent overview [47].…”

Section: What Is Nkdmentioning

confidence: 99%

“…In theory, NKD could present an increased risk for malignancy and there have been a few identified in individuals with NKD, particularly EBV-driven [59,60] and HPV-driven [31] cancers and as such most reported appear to be virally-driven. An overview of these concerns has been reviewed and commented upon by others [47]. For now, the malignancy risk is more theoretical, and as NKD patients are collected and followed for prolonged periods more clarity will be obtained.…”

Section: Getting the Nkd Diagnosis Right And The Index Of Suspicionmentioning

confidence: 99%

“…I do encourage patients to maintain adequate nutrition and other evidence-supported general measures that promote immune function, but with the explanation that they are unlikely to specifically help with the patient's NKD. I do recommend regular and recommended health screenings, especially as advised for the conservative surveillance of cancer screening given the mostly theoretical connection of reduced NK cell activities to cancer susceptibility (the association to which has been considered in detail elsewhere [47]).…”

Section: Management and Treatment Concepts In Nkdmentioning

confidence: 99%

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How I Manage Natural Killer Cell Deficiency

Orange

2019

J Clin Immunol

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Natural killer (NK) cell deficiency (NKD) is a subset of primary immunodeficiency disorders (PID) in which an abnormality of NK cells represents a major immunological defect resulting in the patient's clinical immunodeficiency. This is distinct from a much larger group of PIDs that include an NK cell abnormality as a minor component of the immunodeficiency. Patients with NKD most frequently have atypical consequences of herpesviral infections. There are now 6 genes that have been ascribed to causing NKD, some exclusively and others that also cause other known immunodeficiencies. This list has grown in recent years and as such the mechanistic and molecular clarity around what defines an NKD is an emerging and important field of research. Continued increased clarity will allow for more rational approaches to the patients themselves from a therapeutic standpoint. Having evaluated numerous individuals for NKD, I share my perspective on approaching the diagnosis and managing these patients.

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“…There are different activating receptors on the surface of NK cells comprising: Natural killer receptors (NCRs), NKG2D, and CD16 (FcγRIII) (2,3). It is shown that decreased activity of peripheral blood lymphocyte specially NK cells is associated with higher cancer risk (4)(5)(6). Of note, the inhibitory effect of the tumor microenvironment might also decline the effector functioning of the NK cells by downregulation of activating receptors such as NCRs (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Expression and Purification of a Bispecific Antibody against CD16 and Hemagglutinin Neuraminidase (HN) in E. Coli for Cancer Immunotherapy

et al. 2020

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Background: Immunotherapy of cancer by bispecific antibodies (bsAb) is an attractive approach for retargeting immune effector cells including natural killer (NK) cells to the tumor if the proper expression and purification of the bsAb for such applications could be addressed. Herein, we describe E. coli expression of a recombinant bsAb (bsHN-CD16) recognizing NK-CD16 and hemagglutinin neuraminidase (HN) of Newcastle Disease Virus (NDV). This bsAb might be efficient for ex vivo stimulation of NK cells via coupling to HN on the surface of the NDV-infected tumor cells. Methods: A bsAb-encoding pcDNA3.1 vector (anti-HN scFv-Fc-anti-CD16 scFv) was used as a template, and the scFv segments (after enzymatic digestion and cutting of the Fc part) were rejoined to construct the Fc-deprived bsAb (anti-HN scFv-anti-CD16 scFv; bsHN-CD16). The constructed bsHN-CD16 was inserted into the HindIII and BamHI site of the T7 promoter-based pET28a plasmid. Following restriction analyses and DNA sequencing to confirm the cloning steps, bsHN-CD16 encoding pET28a was transformed into the E. coli (Rosetta DE3 strain), induced for protein expression by IPTG, and the protein was purified under native condition by Ni/NTA column using imidazole. Results: Analyses by SDS-PAGE and Western Blotting using Rabbit anti-human whole IgG-HRP conjugate, confirmed the expression and purification of the bsAb with the expected full size of 55 kDa and yields around 8% of the total protein. Conclusions: Results showed efficient production of the bsAb in E. coli for future large-scale purification.

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Does Natural Killer Cell Deficiency (NKD) Increase the Risk of Cancer? NKD May Increase the Risk of Some Virus Induced Cancer

Cited by 34 publications

References 33 publications

Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID

Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID

How I Manage Natural Killer Cell Deficiency

Expression and Purification of a Bispecific Antibody against CD16 and Hemagglutinin Neuraminidase (HN) in E. Coli for Cancer Immunotherapy

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