Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery

Angka, Leonard; Khan, Saad; Kilgour, Marisa K.; Xu, Rebecca; Kennedy, Michael A.; Auer, Rebecca C.

doi:10.3390/ijms18081787

Cited by 62 publications

(67 citation statements)

References 137 publications

(158 reference statements)

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“…Surgical resection is currently the most effective treatment strategy for patients with an operable pancreatic tumor 27 The similar outcomes between these groups suggests immunotherapies like GVAX may not provide additional benefits in the surgical setting despite the significant tumor debulking associated with surgical resection. It is unclear whether this is a consequence of the immunosuppressive environment associated with surgical stress 10,30,31 or other factors associated with PDAC. However, this result provides a proof-of-concept and further emphasizes the need for models that accurately depict surgical resection of PDAC so that the timing, dose and full efficacy of combination therapies can be adequately explored prior to initiating clinical trials.…”

Section: Discussionmentioning

confidence: 99%

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

Baxter

Souza

Tai

et al. 2020

Preprint

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Background:Although surgery provides the greatest therapeutic benefit to eligible pancreatic ductal adenocarcinoma (PDAC) patients it does not significantly improve survival for the majority of patients. Unfortunately our understanding of the therapeutic benefit of combining surgery with different treatment modalities including promising immunotherapeutics is limited by the current lack of easily adopted surgical models. The purpose of this study was to develop a surgically resectable model of PDAC in immunocompetent mice for use in preclinical investigations. Materials and Methods:Surgically resectable orthotopic tumors were generated by injecting Pan02 cells into the tail of the pancreas. Fifteen days post implantation the primary tumors and tail of the pancreas were resected by laparotomy while preserving the spleen. Splenic function, tumor growth, immune phenotyping and survival were assessed following surgical resection of the primary tumor mass. Results:As expected orthotopic tumor implants recapitulated many of the major histological hallmarks of PDAC including disrupted lobular structure and vascular invasion. Preservation of splenic immune cell viability and function was not associated with improved survival following surgery alone. However, pre-operative vaccination with GVAX was associated with improved survival which was not impacted by surgery. Conclusion:This represents the first murine model of surgically resectable murine model of PDAC which recapitulates known pathological hallmarks of human disease in an immune competent model while allowing spleen preservation. This relatively simple and easily adopted approach provides an ideal platform to examine the efficacy of potential immunotherapy combinations for PDAC surgery patients.3

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Section: Discussionmentioning

confidence: 99%

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

Baxter

Souza

Tai

et al. 2020

Preprint

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“…Increased metastatic disease or recurrence following surgery has been widely observed in humans and recapitulated in animal models (49). In addition to unintentional mechanical dissemination and altered proliferation and signaling in tumor cells, it is now clear that surgery compromises NK cell functions, providing an opportunity for tumor spread and growth (49)(50)(51)(52)(53)(54). Several mechanisms contribute to NK cell dysfunction following surgery, including soluble inflammatory mediators and immunomodulatory cells such as myeloid-derived suppressor cells (MDSCs), which arise by emergency myelopoiesis following surgery (49)(50)(51).…”

Section: Nk Cells In Cancer Immunosurveillancementioning

confidence: 99%

Killers 2.0: NK cell therapies at the forefront of cancer control

Hodgins

Khan

Park

et al. 2019

Journal of Clinical Investigation

166

127

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The existence of immune cells that mediate cellular cytotoxicity without prior activation was determined by multiple groups who reported the spontaneous killing of tumor cells by lymphocytes from unimmunized mice (1-3). We now know that these cells with natural cytotoxicity, or natural killer (NK) cells, are important mediators of cancer immunosurveillance. NK cells are a heterogeneous population, and in humans they have been historically divided into IFN-γ-producing CD56 hi CD16 + and cytotoxic CD56 lo CD16 hi (4), whereas in mice they are grouped according to their expression of CD27 and CD11b (5), although it is now clear that the complexity is much higher. Distinct NK cell subsets play different roles in tumor immunity and cancer immunotherapy, as reviewed in Stabile et al. (6). NK cells are equipped with many receptors that tightly regulate their activation and allow them to discriminate between "normal" and "dangerous" cells (7). In addition to regulating NK cell activation, signals coming from activating and inhibitory receptors also tune the steady-state responsiveness of NK cells to future stimuli, in a process called NK cell education (reviewed in refs. 8, 9). Inhibitory receptors, such as killer-cell immunoglobulinlike receptors (KIRs), deliver negative signals that prevent NK cell autoreactivity. KIRs and other inhibitory receptors recognize MHC I molecules, whose absence may result in NK activation, the so-called "missing-self recognition" (10, 11). Later studies showed that lack of MHC expression was not sufficient or necessary to induce NK activation; rather, signaling from activating receptors was required. Broadly speaking, activating receptors, including NKG2D, provide activating signals upon binding to stress-induced ligands on target cells, which is referred to as "induced-self recognition" (12, 13). Ultimately, NK activation depends on the balance between activating and inhibitory signals triggered by these receptors binding their ligands. When activating signals prevail, NK cells respond, whereas when inhibitory signaling is stronger, NK cells do not respond. Healthy cells, with some exceptions (14-16), express low levels of activating ligands and an abundance of inhibitory ligands and therefore are not attacked by NK cells. On the other hand, tumor cells often acquire expression of NK cellactivating ligands and/or lose expression of MHC molecules. NK cells sense and respond to changes in the repertoire of molecules expressed on the surface of healthy cells during cellular transformation. This positions NK cells as important sentinels against cancer and as prime targets for cancer immunotherapy (17).

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“…The causes of dysfunctional NK cells can be broadly divided into two main categories: (1) quantitative de iciencies with low numbers or absent NK cells and (2) qualitative de iciencies with abnormal function of NK cells. The etiological causes and the associations of quantitative as well as qualitative NK cell de iciencies are shown in tables 2 and 3 [31,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52].…”

Section: Nk Cell Function and Dysfunctionmentioning

confidence: 99%