Harnessing Natural Killer Cells in Non-Small Cell Lung Cancer

Russell, Éilis; Conroy, Melissa J.; Barr, Martin P.

doi:10.3390/cells11040605

Cited by 16 publications

(9 citation statements)

References 102 publications

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“…After GSEA analysis, significant enrichment was detected in signatures promoting an active immune response ( Figure 3 B), including signatures of the TNF superfamily, which is known to promote a proinflammatory immune response and mediates signalling responsible for proliferation, differentiation, and effector functions of immune cells ( Figure 3 B) [ 27 , 28 ]. Moreover, the complement pathway has been implicated enhancing T-cell function and proliferation [ 29 , 30 ], and NK cells play a crucial role in antitumour response [ 31 , 32 ], illustrating the importance of enrichment in NK cell functions ( Figure 3 B). These observations further strengthen our findings that EGFR inhibition not only affects T-cell activity, but also stimulates an increased response of the immune cell infiltrate overall.…”

Section: Resultsmentioning

confidence: 99%

EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

Selenz

Compes

Nill

et al. 2022

Cancers

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EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC.

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Section: Resultsmentioning

confidence: 99%

EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

Selenz

Compes

Nill

et al. 2022

Cancers

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“…In non-small cell lung cancer, the function of NK cells has been shown to be significantly impaired. Therefore, immunotherapy targeting NK cells has become a therapeutic concept for this type of cancer (231). One of the reasons for the anti-tumor immune activity of NK cells is attributed to the binding of its surface-activated receptor natural killer cell group 2D (NKG2D) to MHC class I chain-related protein A/B (MICA/ B), an NKG2D ligand on the surface of tumor cells, thus activating NK cell function and enables NK cells to kill tumor cells (232).…”

Section: Regulation Of Nk Cells By Adam17mentioning

confidence: 99%

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

et al. 2022

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ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.

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“…In humans, the major population of lung NK cells is CD56 bright CD16 − and they show a relatively poor response to target cells but produce more cytokines than peripheral blood NK cells. 102 Tissue-resident NK cells in the lung also highly express CCL5, MIP-1β, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are chemokines that shape cell migration and recruit other immune cells. 103 In the lung, tissue-resident NK cells expressing αEβ7 are located in the alveolar epithelium, where they bind to E-cadherin.…”

Section: Nk Cell Trafficking and Homing At Steady Statementioning

confidence: 99%

Natural killer cell homing and trafficking in tissues and tumors: from biology to application

Ran

Lin

Tian

et al. 2022

Sig Transduct Target Ther

106

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Natural killer (NK) cells, a subgroup of innate lymphoid cells, act as the first line of defense against cancer. Although some evidence shows that NK cells can develop in secondary lymphoid tissues, NK cells develop mainly in the bone marrow (BM) and egress into the blood circulation when they mature. They then migrate to and settle down in peripheral tissues, though some special subsets home back into the BM or secondary lymphoid organs. Owing to its success in allogeneic adoptive transfer for cancer treatment and its “off-the-shelf” potential, NK cell-based immunotherapy is attracting increasing attention in the treatment of various cancers. However, insufficient infiltration of adoptively transferred NK cells limits clinical utility, especially for solid tumors. Expansion of NK cells or engineered chimeric antigen receptor (CAR) NK cells ex vivo prior to adoptive transfer by using various cytokines alters the profiles of chemokine receptors, which affects the infiltration of transferred NK cells into tumor tissue. Several factors control NK cell trafficking and homing, including cell-intrinsic factors (e.g., transcriptional factors), cell-extrinsic factors (e.g., integrins, selectins, chemokines and their corresponding receptors, signals induced by cytokines, sphingosine-1-phosphate (S1P), etc.), and the cellular microenvironment. Here, we summarize the profiles and mechanisms of NK cell homing and trafficking at steady state and during tumor development, aiming to improve NK cell-based cancer immunotherapy.

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Harnessing Natural Killer Cells in Non-Small Cell Lung Cancer

Cited by 16 publications

References 102 publications

EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

Natural killer cell homing and trafficking in tissues and tumors: from biology to application

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