Natural Killer Cell IFNγ Secretion is Profoundly Suppressed Following Colorectal Cancer Surgery

Angka, Leonard; Martel, Andre B.; Kilgour, Marisa K.; Jeong, Ahwon; Sadiq, Manahil; Souza, Christiano Tanese de; Baker, Laura; Kennedy, Michael A.; Kekre, Natasha; Auer, Rebecca C.

doi:10.1245/s10434-018-6691-3

Cited by 76 publications

(81 citation statements)

References 53 publications

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“…As a possible solution, we present methodologies for parallel assessment of immune cell receptor expression, signaling protein activity, and cytokine production in whole blood-derived NK cells. We have demonstrated the feasibility of these assays through the detection of target protein expression in both healthy and disease states (namely solid malignancies), the reproducibility of these assays in patient cohorts despite inherent inter-patient heterogeneity, and the validity of these assays in that our results are comparable to those previously described in the literature (2,12,32,(34)(35)(36)(37)(38)(39). They are simple, timeefficient, and allow for the assessment of any peripheral immune cell population using a minimal volume of whole blood.…”

Section: Discussionsupporting

confidence: 57%

A Comprehensive Assessment of Human Natural Killer Cell Phenotype and Function in Whole Blood

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Tennakoon

et al. 2020

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The majority of data on human Natural Killer (NK) cell phenotype and function has been generated using cryopreserved peripheral blood mononuclear cells (PBMCs). However, cryopreservation can have adverse effects on PBMCs. In contrast, investigating immune cells in whole blood can reduce the time, volume of blood required, and potential artifacts associated with manipulation of the cells. Whole blood collected from healthy donors and cancer patients was processed by three separate protocols that can be used independently or in parallel to assess extracellular receptors, intracellular signaling protein phosphorylation, and intracellular and extracellular cytokine production in human NK cells. To assess extracellular receptor expression, 200 µL of whole blood was incubated with an extracellular staining (ECS) mix and cells were subsequently fixed and RBCs lysed prior to analysis. The phosphorylation status of signaling proteins was assessed in 500 µL of whole blood following co-incubation with interleukin (IL)-2/12 and the ECS mix for 20 minutes prior to cell fixation and RBC lysis and subsequent permeabilization for staining with an intracellular staining (ICS) mix. Cytokine production (IFNγ) was similarly assessed by incubating 1 mL of whole blood with PMA-ionomycin or IL-2/12 prior to incubation with ECS and subsequent ICS antibodies. In addition, plasma was collected from stimulated samples prior to ECS for quantification of secreted IFNγ by ELISA. Results were consistent, despite inherent interpatient variability. Although we did not investigate an exhaustive list of targets, this approach enabled quantification of representative ECS surface markers including activating (NKG2D and DNAM-1) and inhibitory (NKG2D, PD-1, TIGIT, and TIM-3) receptors, cytokine receptors (CD25, CD122, CD132, and CD212) and ICS markers associated with NK cell activation following stimulation, including signaling protein phosphorylation (p-STAT4, p-STAT5, p-p38 MAPK, p-S6K) and IFNγ in both healthy donors and cancer patients. In addition, we compared extracellular receptor expression using whole blood versus cryopreserved PBMCs and observed a significant difference in the expression of almost all receptors. The methods presented permit a relatively rapid parallel assessment of immune cell receptor expression, signaling protein activity, and cytokine production in a minimal volume of whole blood from both healthy donors and cancer patients.

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Section: Discussionsupporting

confidence: 57%

A Comprehensive Assessment of Human Natural Killer Cell Phenotype and Function in Whole Blood

Market

Tennakoon

et al. 2020

Preprint

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“…These include deleterious processes due to perioperative unregulated paracrine, endocrine, immunological, and coagulation responses. In addition, surgery itself can cause a dysfunction of the immunosurveillance through a reduced anti‐metastatic capacity of NK cells and CTLs that has been documented in both human patients and animal models …”

Section: Discussionmentioning

confidence: 99%

Transfusion of red blood cells does not impact progression‐free and overall survival after surgery for ovarian cancer

et al. 2019

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BACKGROUND: Allogeneic red blood cells (RBCs) have the potential to impact the immunosurveillance of the recipient and may therefore increase the risk of recurrence after cancer surgery. In this article the relationship between perioperative RBC transfusion and the risk of recurrence after ovarian cancer surgery is examined.STUDY DESIGN AND METHODS: This is a retrospective cohort analysis of a prospective database of patients who underwent surgery due to primary ovarian cancer between 2006 and 2014 and who had no residual disease after surgery. Patients who did and did not receive perioperative RBC transfusion were compared. The primary endpoint was progression-free survival (PFS). Propensity score matching (PSM) and Cox proportional hazards regression (CPH) was used to control for between-group differences of prognostic determinants. RESULTS:A total of 529 patients with a median followup of 51.4 months (95% CI, 46.1-56.5) were eligible for analysis. Of those, 408 patients (77.1%) received allogeneic, leukoreduced RBCs with a median of 4 units (IQR, 2-6) per patient. There was a strong selection bias of prognostic determinants between patients with and without transfusion. In unadjusted analysis, transfusion of RBCs was associated with an increased risk of cancer recurrence (hazard ratio [HR] of PFS 2.71 [95% CI, 1.94-3.77], p < 0.001). After bias reduction, transfusion of RBCs was no longer associated with an increased risk of cancer recurrence, neither in PSM-adjusted (HR 1.03 [95% CI, 0.59-1.80], p = 0.91), nor in multivariable CPHadjusted analysis (HR 1.26 [95% CI, 0.85-1.86], p = 0.23).CONCLUSION: Perioperative transfusion of RBCs did not increase the risk of recurrence after ovarian cancer surgery.From the

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“…The seminal 1989 case of NKD in an adolescent female with severe herpesvirus infections (varicella pneumonia, disseminated CMV, and disseminated HSV) revealed how functional NK cell deficiencies have clinical consequences in terms of viral infections (97). Cancer patients are also at risk of viral infections (98), which may be explained, at least in part, by an impairment of NK cell responses often observed in humans and in murine tumor models (99)(100)(101)(102)(103)(104).…”

Section: Nk Cell Dysfunction Is Linked With Increased Viral Susceptibmentioning

confidence: 99%

Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies

et al. 2020

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Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.

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Natural Killer Cell IFNγ Secretion is Profoundly Suppressed Following Colorectal Cancer Surgery

Abstract: NKA is significantly suppressed for up to two months following surgery in CRC patients, a degree of surgery-induced immunosuppression far worse than previously reported.

Cited by 76 publications

References 53 publications

A Comprehensive Assessment of Human Natural Killer Cell Phenotype and Function in Whole Blood

A Comprehensive Assessment of Human Natural Killer Cell Phenotype and Function in Whole Blood

Transfusion of red blood cells does not impact progression‐free and overall survival after surgery for ovarian cancer

Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies

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