Diverse Anti-Tumor Immune Potential Driven by Individual IFNα Subtypes

Abstract

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.

Tumour draining lymph node-generated CD8 T cells play a role in controlling lung metastases after a primary tumour is removed but not when adjuvant immunotherapy is used

“…We, and others, have shown that tumour dLNs have been shown to harbour vital tumour-specific T cells [5,7,8,16,17,21,22]. Notably, after partial tumour resection tumour antigen presentation continues in the dLN for 7 to 14 days [7] driving the development of CD8 T effector memory cell responses to reduce local residual disease or protect against tumour development on re-challenge [11,12].…”

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

“…Type-I interferons (IFN-Is) are a functionally diverse family of cytokines that play a crucial role in generating potent innate and adaptive immune responses against cancer [ 154 ]. IFN-Is are indispensable to anti-tumour immunity by enhancing intra-tumoural CTL-DC crosstalk [ 155 ], as well as the augmentation of NK and M1 macrophage activity in the TME [ 156 , 157 ].…”

“…More recently, Effern et al noted that recurring tumours with significant loss of antigen expression were associated with more intense IFN signalling [ 169 ], suggesting that tumour dedifferentiation as a mechanism of immune evasion may be driven by overexuberant anti-tumour responses within the TME. This may also be confounded by the functional heterogeneity of IFN-Is, where specific IFNα subtypes are clearly more potent primers of the anti-tumour immune response, although this has only been explored in murine models [ 154 ].…”

Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease

“…Increasing tumor cell production of IFNa is another approach, and a very recent study demonstrated that IFNa subtypes are not all equal in their antitumor properties. B16 melanoma cells were engineered to overexpress IFNa2, a4, a5, a6, or a9, but only IFNa2-and a9expressing tumors were effectively controlled in an adaptiveimmunity dependent manner (247). Other studies have used a variety of genetic engineering methods to augment IFNa production in the tumor microenvironment and improve antitumor immunity (248)(249)(250)(251).…”