The importance of type I interferon in orchestrating the cytotoxic T-cell response to cancer

Both type I interferon (IFN-I) and CD4⁺ T-cell help are required to generate effective CD8⁺ T-cell responses to cancer. We here outline based on existing literature how IFN-I signaling and CD4⁺ T-cell help are connected. Both impact on the functional state of dendritic cells (DCs), particularly conventional (c)DC1. The cDC1s are critical for crosspresentation of cell-associated antigens and for delivery of CD4⁺ T-cell help for cytotoxic T-lymphocyte (CTL) effector and memory differentiation. In infection, production of IFN-I is prompted by pathogen-associated molecular patterns (PAMPs), while in cancer it relies on danger-associated molecular patterns (DAMPs). IFN-I production by tumor cells and pDCs in the tumor micro-environment (TME) is often limited. IFN-I signals increase the ability of migratory cDC1s and cDC2s to transport tumor antigens to tumor-draining lymph nodes (tdLNs). IFN-I also enables cDC1s to form and sustain the platform for help delivery by stimulating the production of chemokines that attract CD4⁺ and CD8⁺ T cells. IFN-I promotes delivery of help in concert with CD40 signals by additive and synergistic impact on cross-presentation and provision of critical costimulatory and cytokine signals for CTL effector and memory differentiation. The scenario of CD4⁺ T-cell help therefore depends on IFN-I signaling. This scenario can play out in tdLNs as well as in the TME, thereby contributing to the cancer immunity cycle. The collective observations may explain why both IFN-I and CD4⁺ T-cell help signatures in the TME correlate with good prognosis and response to PD-1 targeting immunotherapy in human cancer. They also may explain why a variety of tumor types in which IFN-I signaling is attenuated, remain devoid of functional CTLs.