Natural Killers Are Made Not Born: How to Exploit NK Cells in Lung Malignancies

Abstract

In recent years, progress has been made in the characterization of natural killer (NK) cells in lung malignancies, and we have now gained a better understanding of the frequency, localization, phenotype, and functional status of NK cells infiltrating these tumors. NK cell subset recruited in lung cancer is mainly capable of producing relevant cytokines rather than exerting direct cancer cell killing. Thus, the relevance of NK cells in tumor microenvironment might also go beyond the killing of tumor cells, being NK cells endowed with regulatory functions toward an ample array of immune effectors. Nevertheless, boosting their cytotoxic functions and redirecting the migration of cytotoxic NK cell subset to the tumor site might open new therapeutic avenues for lung cancer. Also, we believe that a deeper investigation into the impact of both conventional (e.g., chemotherapy) or new therapies (e.g., anti-immune checkpoints mAbs) on NK cell homeostasis in lung cancer patients is now required.

Keywords: cytokines; cytotoxicity; lung cancer; natural killer cells; tumor microenvironment.

Figure 1

Natural killer (NK) cell subsets in healthy and neoplastic lung tissues. Human healthy lung tissues are mainly populated by CD56^dimCD16⁺ NK cells but also present a small subset of CD56^bright NK cells expressing CD69, a marker of tissue-residency. Conversely, NSCLC tissues were found to be infiltrated by an NK cell population highly enriched in CD56^brightCD16^negPerforin^low/negKIR⁺ cells. The reasons for such an accumulation are not clear. They may derive from (1) extravasation of PB NK cells from newly formed blood vessels and/or (2) migration of CD56^bright NK cells from the adjacent normal lung tissue in response to upregulated chemokines (CXCL9/CXCL10) in the neoplastic tissues. Moreover, (3) they may be recruited by chemokines (such as CCL19/CCL21) expressed in tertiary lymphoid structures or a lymphoid-like stroma via high endothelial venules (HEV), which represent a new gateway for lymphocyte entry into the tumor. Finally, (4) a local expansion from NK cell precursors (NKP) (21)/immature NK cells cannot be excluded. Noteworthy, the ratio of tissue-resident versus circulating/non-residing NK cells in neoplastic tissue has so far not sufficiently been deeply investigated.

Figure 2

Possible conversion of lung cancer-infiltrating natural killer (NK) cells into highly cytotoxic killer cells upon administration of NK-activating drugs. (A) NK cells isolated from NSCLC tissues display phenotypic features similar to those of peripheral blood (PB) CD56^bright NK cells, with the exception of KIRs, that can be detectable on these cells. Similarly to PB CD56^bright NK cells, they are endowed with high proliferative potential but impaired in their cytotoxic capability. In addition, it is not clear whether NK cells infiltrating human lung tumors express other immune checkpoints (such as PD-1), which might further contribute to their poor cytolytic activity. (B) Upon activation with stimulating cytokines (recombinant IL-15, IL-2) or mAbs-blocking inhibitory receptors (e.g., anti-NKG2A, which is highly expressed on these cells, or anti-PD1), intratumoral NK cells may proliferate in situ and modify their phenotype acquiring strong cytolytic capabilities against cancer cells. (C) Administration of cytokines or other NK-activating drugs, currently available, can upregulate the expression of cytolytic granules on expanded tumor-infiltrating NK cells but also induce higher levels of KIR inhibitory receptors: this might be circumvented by administration of anti-KIRs mAbs. It remains to be investigated whether in vivo stimulation of lung cancer-infiltrating NK cells can upregulate on these cells the expression of activating receptors (e.g., CD16), immune checkpoints, or markers of tissue residency.