Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis.

The liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and nonredundant action of two innate lymphocyte subpopulations, conventional natural killer cells (cNKs) and tissue-resident type I innate lymphoid cells (trILC1s), is essential for antimetastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 controls metastatic seeding, whereas cNKs restrain outgrowth. Whereas the killing capacity of trILC1s was not affected by the metastatic microenvironment, the phenotype and function of cNK cells were affected in a cancer type-specific fashion. Thus, individual cancer cell lines orchestrate the emergence of unique cNK subsets, which respond differently to tumor-derived factors. Our findings will contribute to the development of therapies for liver metastasis involving hepatic innate cells.

Innate lymphoid cells as regulators of the tumor microenvironment.

As crucial players in innate immunity, Innate Lymphoid Cells (ILCs) have been distinctly associated with either tumor-promoting or tumor-inhibiting activities. This dichotomy arises from the high degree of heterogeneity and plasticity between the ILC family subsets. Also, the tissue microenvironment is crucial for the function of ILCs. Especially within the tumor niche, each of the ILC subsets participates in a complex network of interactions with other cells and molecules. Although extensive research has unraveled several aspects of the crosstalk ILCs establish with the tumor microenvironment (TME), numerous questions remain to be answered. Here, we will discuss a role for the different ILC subsets that goes beyond their direct effects on the tumor cells. Instead, we will highlight the ability of ILCs to communicate with the surrounding milieu and the impact this has on tumor progression.

The Interplay Between Innate Lymphoid Cells and the Tumor Microenvironment.

The multifaceted roles of Innate Lymphoid Cells (ILC) have been widely interrogated in tumor immunity. Whereas, Natural Killer (NK) cells possess undisputable tumor-suppressive properties across multiple types of cancer, the other ILC family members can either promote or inhibit tumor growth depending on the environmental conditions. The differential effects of ILCs on tumor outcome have been attributed to the high degree of heterogeneity and plasticity within the ILC family members. However, it is now becoming clear that ILCs responses are shaped by their dynamic crosstalk with the different components of the tumor microenvironment (TME). In this review, we will give insights into the molecular and cellular players of the ILCs-TME interactions and we will discuss how we can use this knowledge to successfully harness the activity of ILCs for anticancer therapies.

Restoration of Natural Killer Cell Antimetastatic Activity by IL12 and Checkpoint Blockade.

Immune checkpoint therapies target tumor antigen-specific T cells, but less is known about their effects on natural killer (NK) cells, which help control metastasis. In studying the development of lung metastases, we found that NK cells lose their cytotoxic capacity and acquire a molecular signature defined by the expression of coinhibitory receptors. In an effort to overcome this suppressive mechanism, we evaluated NK cell responses to the immunostimulatory cytokine IL12. Exposure to IL12 rescued the cytotoxicity of NK cells but also led to the emergence of an immature NK cell population that expressed high levels of the coinhibitory molecules PD-1, Lag-3, and TIGIT, thereby limiting NK cell-mediated control of pulmonary metastases. Notably, checkpoint blockade therapy synergized with IL12 to fully enable tumor control by NK cells, demonstrating that checkpoint blockers are not only applicable to enhance T cell-mediated immunotherapy, but also to restore the tumor-suppressive capacity of NK cells. Cancer Res; 77(24); 7059-71. ©2017 AACR.

Phenotypic switch of CD8(+) T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells.

CD8(+) T cells controlling pathogens or tumors must function at sites where oxygen tension is frequently low, and never as high as under atmospheric culture conditions. However, T-cell function in vivo is generally analyzed indirectly, or is extrapolated from in vitro studies under nonphysiologic oxygen tensions. In this study, we delineate the role of physiologic and pathologic oxygen tension in vitro during reactivation and differentiation of tumor-specific CD8(+) T cells. Using CD8(+) T cells from pmel-1 mice, we observed that the generation of CTLs under 5% O2, which corresponds to physioxia in lymph nodes, gave rise to a higher effector signature than those generated under atmospheric oxygen fractions (21% O2). Hypoxia (1% O2) did not modify cytotoxicity, but decreasing O2 tensions during CTL and CD8(+) tumor-infiltrating lymphocyte reactivation dose-dependently decreased proliferation, induced secretion of the immunosuppressive cytokine IL-10, and upregulated the expression of CD137 (4-1BB) and CD25. Overall, our data indicate that oxygen tension is a key regulator of CD8(+) T-cell function and fate and suggest that IL-10 release may be an unanticipated component of CD8(+) T cell-mediated immune responses in most in vivo microenvironments.