Deciphering the Immunological Phenomenon of Adaptive Natural Killer (NK) Cells and Cytomegalovirus (CMV).

Natural killer (NK) cells play a significant and vital role in the first line of defense against infection through their ability to target cells without prior sensitization. They also contribute significantly to the activation and recruitment of both innate and adaptive immune cells through the production of a range of cytokines and chemokines. In the context of cytomegalovirus (CMV) infection, NK cells and CMV have co-evolved side by side to employ several mechanisms to evade one another. However, during this co-evolution the discovery of a subset of long-lived NK cells with enhanced effector potential, increased antibody-dependent responses and the potential to mediate immune memory has revolutionized the field of NK cell biology. The ability of a virus to imprint on the NK cell receptor repertoire resulting in the expansion of diverse, highly functional NK cells to this day remains a significant immunological phenomenon that only occurs in the context of CMV. Here we review our current understanding of the development of these NK cells, commonly referred to as adaptive NK cells and their current role in transplantation, infection, vaccination and cancer immunotherapy to decipher the complex role of CMV in dictating NK cell functional fate.

Type I interferon subtypes differentially activate the anti-leukaemic function of natural killer cells.

Natural killer (NK) cells have an intrinsic ability to detect and eliminate leukaemic cells. Cellular therapies using cytokine-activated NK cells have emerged as promising treatments for patients with advanced leukaemia. However, not all patients respond to current NK cell therapies, and thus improvements in efficacy are required. Type I interferons (IFN-I) are a family of potent immunomodulatory cytokines with a known ability to modulate NK cell responses against cancer. Although the human IFN-I family comprises 16 distinct subtypes, only IFNα2 has been widely explored as an anti-cancer agent. Here, we investigated the individual immunomodulatory effects each IFNα subtype and IFNß had on NK cell functionality to determine whether a particular subtype confers enhanced effector activity against leukaemia. Importantly, IFNα14 and IFNß were identified as superior activators of NK cell effector function in vitro. To test the ability of these subtypes to enhance NK cell activity in vivo, IFN-I stimulation was overlaid onto a standard ex vivo expansion protocol to generate NK cells for adoptive cell therapy. Interestingly, infusion of NK cells pre-activated with IFNα14, but not IFNß, significantly prolonged survival in a preclinical model of leukaemia compared to NK cells expanded without IFN-I. Collectively, these results highlight the diverse immunomodulatory potencies of individual IFN-I subtypes and support further investigation into the use of IFNα14 to favourably modulate NK cells against leukaemia.

Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression.

Immunotherapy has revolutionised the treatment of cancers by harnessing the power of the immune system to eradicate malignant tissue. However, it is well recognised that some cancers are highly resistant to these therapies, which is in part attributed to the immunosuppressive landscape of the tumour microenvironment (TME). The contexture of the TME is highly heterogeneous and contains a complex architecture of immune, stromal, vascular and tumour cells in addition to acellular components such as the extracellular matrix. While understanding the dynamics of the TME has been instrumental in predicting durable responses to immunotherapy and developing new treatment strategies, recent evidence challenges the fundamental paradigms of how tumours can effectively subvert immunosurveillance. Here, we discuss the various immunosuppressive features of the TME and how fine-tuning these mechanisms, rather than ablating them completely, may result in a more comprehensive and balanced anti-tumour response.

Directing the Future Breakthroughs in Immunotherapy: The Importance of a Holistic Approach to the Tumour Microenvironment.

Immunotherapy has revolutionised the treatment of cancers by exploiting the immune system to eliminate tumour cells. Despite the impressive response in a proportion of patients, clinical benefit has been limited thus far. A significant focus to date has been the identification of specific markers associated with response to immunotherapy. Unfortunately, the heterogeneity between patients and cancer types means identifying markers of response to therapy is inherently complex. There is a growing appreciation for the role of the tumour microenvironment (TME) in directing response to immunotherapy. The TME is highly heterogeneous and contains immune, stromal, vascular and tumour cells that all communicate and interact with one another to form solid tumours. This review analyses major cell populations present within the TME with a focus on their diverse and often contradictory roles in cancer and how this informs our understanding of immunotherapy. Furthermore, we discuss the role of integrated omics in providing a comprehensive view of the TME and demonstrate the potential of leveraging multi-omics to decipher the underlying mechanisms of anti-tumour immunity for the development of novel immunotherapeutic strategies.

IFNß Is a Potent Adjuvant for Cancer Vaccination Strategies.

Cancer vaccination drives the generation of anti-tumor T cell immunity and can be enhanced by the inclusion of effective immune adjuvants such as type I interferons (IFNs). Whilst type I IFNs have been shown to promote cross-priming of T cells, the role of individual subtypes remains unclear. Here we systematically compared the capacity of distinct type I IFN subtypes to enhance T cell responses to a whole-cell vaccination strategy in a pre-clinical murine model. We show that vaccination in combination with IFNß induces significantly greater expansion of tumor-specific CD8+ T cells than the other type I IFN subtypes tested. Optimal expansion was dependent on the presence of XCR1+ dendritic cells, CD4+ T cells, and CD40/CD40L signaling. Therapeutically, vaccination with IFNß delayed tumor progression when compared to vaccination without IFN. When vaccinated in combination with anti-PD-L1 checkpoint blockade therapy (CPB), the inclusion of IFNß associated with more mice experiencing complete regression and a trend in increased overall survival. This work demonstrates the potent adjuvant activity of IFNß, highlighting its potential to enhance cancer vaccination strategies alone and in combination with CPB.

Diverse Anti-Tumor Immune Potential Driven by Individual IFNα Subtypes.

Immunotherapies harnessing T cell immunity have shown remarkable clinical success for the management of cancer. However, only a proportion of patients benefit from these treatments. The presence of type I interferon (IFN) within the tumor microenvironment is critical for driving effective tumor-specific T cell immunity. Individuals can produce 12 distinct subtypes of IFNα, which all signal through a common receptor. Despite reported differences in anti-viral potencies, the concept that distinct IFNα subtypes can improve anti-cancer treatments remains unclear. We tested whether expression of unique IFNα subtypes confined to the tumor microenvironment enhances tumor control. This was systematically evaluated by transplantation of B16 murine melanoma cells secreting five unique IFNα subtypes (B16_IFNα2; B16_IFNα4; B16_IFNα5; B16_IFNα6; B16_IFNα9) into a pre-clinical murine model. We show that IFNα2 and IFNα9 are the only subtypes capable of completely controlling tumor outgrowth, with this protection dependent on the presence of an adaptive immune response. We next determined whether these differences extended to other model systems and found that the adoptive transfer of tumor-specific CD8+ T cells engineered to secrete IFNα9 delays tumor growth significantly and improves survival, whereas no enhanced survival was observed using T cells secreting IFNα4. Overall, our data shows that the expression of distinct IFNα subtypes within the tumor microenvironment results in different anti-tumor activities, and differentially affects the efficacy of a cancer therapy targeting established disease.