Familial cancer: depressed NK-cell cytotoxicity in healthy and cancer affected members

Montelli, Terezinha C. B.; Peraçoli, Maria Terezinha Serrão; Gabarra, Roberto Colichio; Soares, Ana Flávia; Kurokawa, Cilmery Suemi

doi:10.1590/s0004-282x2001000100003

Cited by 12 publications

(8 citation statements)

References 14 publications

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“…This hypothesis is indirectly supported by a study showing that individuals with lower NK cytotoxic activity in peripheral blood had a higher incidence of cancer (n=3,500 with 11-year follow-up) 39 ). Similarly, previous studies showed that impaired NK cell activity was found in family members of patients with different types of cancer ( 40, 41, 42 ). Importantly, such inherited defects in NK cells, APP and Wnt pathways were repeatedly observed between non-cancer and cancer individuals (Fig 2b, Supplementary Fig 9), between TIME-rich and TIME-intermediate/-poor patients (Fig 2a, Supplementary Fig 4, Fig 1d), suggesting that these individuals were highly selected for tumorigenesis and metastasis.…”

Section: Resultssupporting

confidence: 67%

Inherited defects in natural killer cells shape tumor immune microenvironment, clinical outcome and immunotherapy response

Xu¹,

Zou

et al. 2018

Preprint

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27Tumor immune microenvironment (TIME) plays an important role in metastasis and 28 immunotherapy. However, it has been not much known how to classify TIMEs and how TIMEs are 29 genetically regulated. Here we showed that tumors were classified into TIME-rich, -intermediate and -30 poor subtypes which had significant differences in clinical outcomes, abundances of tumor-infiltrating 31 lymphocytes (TILs), degree of key immune programs' activation, and immunotherapy response across 32 13 common cancer types (n= ~6,000). Furthermore, TIME-intermediate/-poor patients had significantly 33 more inherited genetic defects (i.e., functional germline variants) in natural killer (NK) cells, antigen 34 processing and presentation (APP) and Wnt signaling pathways than TIME-rich patients, and so did 35 cancer patients than non-cancer individuals (n=4,500). These results suggested that individuals who 36 had more inherited defects in NK cells, APP and Wnt pathways had higher risk of developing 37 cancers. Moreover, in the 13 common cancers the number of inheritably defected genes of NK 38 cells was significantly negative-correlated with patients' survival, TILs' abundance in TIMEs and 39 immunotherapy response, suggesting that inherited defects in NK cells alone were sufficient to shape 40 TILs' recruitment, clinical outcome and immunotherapy response, highlighting that NK cell activation 41 was required in the 13 cancer types to drive the recruitment of immune troops into TIMEs. Thus, we 42proposed that cancer was a disease of NK cell inherited deficiencies. These results had implications in 43 identifying of high-risk individuals based on germline genomes, implementing precision cancer 44 prevention by adoptive transfer of healthy NK cells, and improving existing immunotherapies by 45 combining of adoptive NK cell transfer (i.e., converting TIME-intermediate/-poor tumors into TIME-46 rich tumors) in and anti-PD-1 or CAR-T therapy. 47 48 49

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Section: Resultssupporting

confidence: 67%

Inherited defects in natural killer cells shape tumor immune microenvironment, clinical outcome and immunotherapy response

Xu¹,

Zou

et al. 2018

Preprint

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“…The study by Imai et al on an 11-year followup of 3,625 residents of a Japanese community for their immune cell profile indicated that medium and high cytotoxic activity of peripheral-blood lymphocytes is correlated with a decrease in cancer risk, whereas low activity is correlated with an elevated cancer risk (5). In their study, Montelli et al concluded that NK-cell activity is decreased in family members of patients with various types of cancer compared to healthy controls of similar parameters (6). Similarly, the study by Dewan et al revealed that NK activity of PBMNCs is lower in breast cancer patients (21).…”

Section: Discussionmentioning

confidence: 98%

“…The detailed results of the PBMNC cell counts, cell expansion details and the percentage of CD3-CD56+ cells are shown in Table I 6 cells, respectively. The average percentage of CD3-CD56+ cells on the day of maximum growth or the day of harvesting in Case I following in vitro expansion was 1.2%, while in Case II it was 65.7%; in Case III it was 28.63%, in Case IV it was 65.9% and in Case V it was 40%.…”

Section: Patient Characteristics and In Vitro Cell Expansionmentioning

confidence: 99%

“…Their role in curtailing cancers and viral infections is currently being used as a therapeutic strategy in the form of autologous immune enhancement therapy (AIET), which has been used in clinical practice in several developed nations, including Japan, since the early 1990s and has undergone numerous randomized clinical trials in lung, gastric, ovarian and liver cancers (1)(2)(3)(4). Evidence has shown that cancer victims have significantly fewer NK cells in their peripheral blood (PB) than normal age-matched controls (5,6). Numerous auto-immune conditions, including multiple sclerosis, systemic lupus erythematosus and type I (auto-immune) diabetes mellitus, have been reported to be associated with a comparatively lower NK-cell profile (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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A comparative analysis of in vitro expansion of natural killer cells of a patient with autoimmune haemolytic anaemia and ovarian cancer with patients with other solid tumours

et al. 2011

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Abstract. The functional profile of natural killer (NK) cells has been reported to be lower in auto-immune haemolytic anaemia (AIHA). In this study, we report a comparative analysis of peripheral blood mononuclear cells (PBMNCs) and the in vitro expansion of NK cells in a patient with AIHA and cancer, with that of other cancer patients without AIHA. PBMNCs and in vitro NK-cell expansion of a 64-year old female patient with ovarian cancer and AIHA was compared with that of four other patients with cancer without AIHA who underwent autologous immune enhancement therapy (AIET). The NK cells were cultured using autologous plasma without feeder layers. The quantities of PBMNCs, NK cells and CD3-CD56+ cells were compared. The average quantity of PBMNCs per ml in Cases I to V were 10.71, 39.2, 49.26, 65.16 and 49.33x10 4 , respectively, and the average maximum count of NK cells was 3. 9, 1730.03, 1824.16, 1058.61 and 761x10 6 , respectively. The average percentage of CD3-CD56+ cells in Cases I to V following in vitro expansion was 1.2, 65.7, 28.63, 65.9 and 40%, respectively. In the present study, probably the first in the literature, the in vitro expansion of NK cells was found to be significantly lower in the AIHA patient. Previously, only a lower NK-cell functional profile was reported. Further studies are required to establish the association between AIHA and NK-cell profile and in vitro expansion, and to find common antibodies between red blood cells (RBCs) and NK cells.

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“…In particular, the lytic unit does not address the matter of NK cell frequency in the assay system; rather, it should be regarded as a reasonable proxy for the percent lysis generated at various E/T ratios. In contrast, an agarose gel or poly-L-lysine hydrobromide polymer-based cell cytotoxicity assay system, in which effector cell/target cell conjugates are made and then the degree of effector cells bound to target cells is measured as a percentage to determine NK cell activity, may resolve the NK cell frequency effect (31,32). This method deals with single-cell activity conceptually equivalent to the lytic index.…”

Section: Discussionmentioning

confidence: 99%

Hemacytotoxicity and natural killer lytic index: New parameters to evaluate natural killer cell immunity for clinical use in cancer

Maeng

Lee

et al. 2017

Oncol Lett

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Abstract. Cytotoxicity assays with patient peripheral blood mononuclear cell (PBMC)-derived natural killer (NK) cells are useful in evaluating the innate immunity of patients with cancer. However, the size of the NK cell population in PBMC preparations may have significant effects on the assay outcome. Therefore, the present study examined the effect of NK cell frequency in a cytotoxicity system to investigate NK cell immunity in post-surgical colorectal cancer patients. For this, hemacytotoxicity was assessed using PBMC preparations, and lymphocyte subset populations were analyzed in samples obtained from 47 patients and 45 healthy volunteers. In addition, a new theoretical parameter, the 'NK lytic index', was termed to represent the per-cell cytotoxicity and compensate for the NK cell frequency effect during PBMC preparations. Notably, the patterns of hemacytotoxicity and NK lytic index did not coincide in follow-up studies with consecutive patients following surgical intervention. In addition, it was determined that NK cell NKG2D expression influences NK lytic index, but not hemacytotoxicity. Transforming growth factor (TGF)-β-bound lymphocytes influenced hemacytotoxicity and NK lytic index. These findings indicate that total cell activity (hemacytotoxicity) is not a sum of per-cell activities (NK lytic indexes), suggesting that clinicians should employ NK lytic index in addition to hemacytotoxicity in order to precisely determine how to enhance NK cell immunity in patients with cancer, either focusing on recovering the number of NK cells or boosting NK cell activity in single cell levels, or both. IntroductionNatural killer (NK) cells, which serve critical roles in cancer immunity, are regarded as the first line of defense to eliminate transformed or malignant tumor cells (1). Therefore, multiple clinical laboratories have examined the implications of NK cell-mediated immunity in cancer and demonstrated that NK cells are functionally impaired in the majority of forms of cancer (2-4). Therefore, clinical attempts to boost endogenous NK cell activity, using biological response modifiers or the adoptive transfer of in vitro activated NK cells, have been investigated for the treatment of patients with cancer (5,6). However, a reliable tool to evaluate NK cell activity on a per-cell basis in each patient should be described prior to clinical application in order to design optimal treatment regimens, particularly since the degree of impaired NK cell activity and its etiology differ from patient to patient (7-9).In vitro cytotoxicity assays have been widely used in clinical laboratories to study NK cell function in patients with cancer. A feature of this assay system is the co-culture of effector cells with their specific target cells over a range of ratios, in which the cytotoxicity of NK cells against their target cells is measured by arithmetic calculation of the number of target cells killed during the given reaction. Purified peripheral NK cells from blood are a favored source of effector cells, but unfraction...

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Familial cancer: depressed NK-cell cytotoxicity in healthy and cancer affected members

Cited by 12 publications

References 14 publications

Inherited defects in natural killer cells shape tumor immune microenvironment, clinical outcome and immunotherapy response

Inherited defects in natural killer cells shape tumor immune microenvironment, clinical outcome and immunotherapy response

A comparative analysis of in vitro expansion of natural killer cells of a patient with autoimmune haemolytic anaemia and ovarian cancer with patients with other solid tumours

Hemacytotoxicity and natural killer lytic index: New parameters to evaluate natural killer cell immunity for clinical use in cancer

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