Tissue‐resident CD69⁺CXCR6⁺ Natural Killer cells with exhausted phenotype accumulate in human non‐small cell lung cancer

Abstract

Natural killer (NK) cells with tissue-residency features (trNK cells) are a new subpopulation of NK cells, which plays an important role in tissue homeostasis. However, the characteristics of trNK cells in the tumor microenvironment (TME) of human cancers remain unclear. Using multicolor flow cytometry, we investigated the quantity, phenotype, and function of trNK cells in biospecimens freshly resected from 60 non-small cell lung cancer (NSCLC) patients. We successfully identified a new CD69 + CXCR6 + trNK subset with an immunomodulatory-like and exhausted phenotype, specifically accumulated in the TME of NSCLC. In vitro experiments showed that CD69 + CXCR6 + trNK cells more readily secreted IFN-γ and TNF-α spontaneously. Furthermore, the production of IFN-γ and TNFα by tumor-infiltrating CD69 + CXCR6 + trNK cells was not induced by their reactivation in vitro, which is analogous to T-cell exhaustion. Finally, we demonstrated that the dysfunction of CD69 + CXCR6 + trNK cells could be partly ameliorated by PD-1 and CTLA-4 blockade. In summary, we identified a new dysfunctional CD69 + CXCR6 + trNK cell subset that specifically accumulates in the TME of NSCLC. Our findings suggest that CD69 + CXCR6 + trNK cells are a promising target for immune checkpoint inhibitors in the treatment of NSCLC.

Modulation of natural killer cell exhaustion in the lungs: the key components from lung microenvironment and lung tumor microenvironment

“…However, once the tumor enters the promotion and progression stage, NK cells exhibit an exhausted phenotype with low cytotoxicity and viability (36). Similarly, intratumor NK cells show an exhausted phenotype, lower IFN-g production, and impaired cytotoxic function in patients with nonsmall cell lung carcinoma (NSCLC) (7,(55)(56)(57). Most recently, Tang et al analyzed human NK cells from 716 patients across 24 tumor types by integrative single-cell sequencing and found that NK cells display tumor-type preferences and are associated with both intrinsic organ properties and factors from the tumor microenvironment.…”

Roles of tissue-resident immune cells in immunotherapy of non-small cell lung cancer

“…NK cells are the first line of defense against environmental destruction, pathogens and cancers, enriched in the tumor microenvironment of NSCLC ( 23 ), lung trNK cells are prone to produce CCL5, MIP-1β, and GM-CSF, which may always alter their microenvironment by attracting other immune cells (e. g., monocytes, T cells, and eosinophils) ( 24 ). A study has shown that tissue-resident CD69 + CXCR6 + NK cells with depletion phenotype accumulate in human non-small cell lung cancer and are a promising target for immune checkpoint inhibitors in the treatment of NSCLC ( 25 ). For DC, a study has shown that DC derived from NSCLC has immunosuppressive effects, and the co-suppressor molecule B7-H3 plays a crucial role in mediating the T cell inhibition of DC under tumor conditions ( 26 ).…”

“…And, it has been found that a tissue-resident CD69 CXCR6 NK cell with an exhaustive phenotype accumulates in NSCLC. Its dysfunction can be partially ameliorated by PD-1 and CTLA-4 blockade ( 25 ). Thus, these findings suggest a close interrelationship between tissue-resident immune cells exhaustion and tumor.…”

“…trNK cells are abundant in the lung and can recognize and kill tumor cells through various mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), natural cytotoxicity receptors (NCRs) and NKG2D (67)(68)(69). trNK cells can also produce cytokines, such as IFN-g, TNF-a, and IL-15, that modulate the TME and promote the activation of other immune cells (24,25).…”

Identification of Tissue-Resident Natural Killer and T Lymphocytes with Anti-Tumor Properties in Ascites of Ovarian Cancer Patients

“…Under certain conditions, NK and T cells also express other inhibitory receptors, such as PD-1, CTLA-4, TIM-3, LAG-3 and TIGIT [ 15 , 16 , 17 ]. These inhibitory receptors, when engaged with their cognate ligand in the effector phase of an immune response, raise the activation threshold and suppress NK cell activation, as well as T cell activation.…”