TIL the end: Tracking T cell clonotype dynamics during adoptive cell therapy.

Understanding the factors that lead to the therapeutic success of adoptive cell therapies using tumor-infiltrating lymphocytes (TIL-ACT) will improve current treatment protocols. In this issue of Immunity, Chiffelle et al. comprehensively compare the dynamics of CD8+ T cell clonotypes during the course of ACT between responding and non-responding patients.

CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours.

Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T cells to directly recognize and kill tumour cells1-3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4-6. The ability of CD4+ effector cells to contribute to antitumour immunity independently of CD8+ T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified7-10. Here, we describe a mechanism whereby a small number of CD4+ T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8+ T cell targeting. The CD4+ effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II+CD11c+ antigen-presenting cells. We show that T helper type 1 cell-directed CD4+ T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4+ T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4+ T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8+ T cells and natural killer cells and advance cancer immunotherapies.

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.

CD8+XCR1neg Dendritic Cells Express High Levels of Toll-Like Receptor 5 and a Unique Complement of Endocytic Receptors.

Conventional dendritic cells (cDC) resident in the lymphoid organs of mice have been classically divided into CD8+ and CD8neg subsets. It is well-established that CD8+ dendritic cells (DCs) and their migratory counterparts in the periphery comprise the cross-presenting cDC1 subset. In contrast, CD8neg DCs are grouped together in the heterogeneous cDC2 subset. CD8neg DCs are relatively poor cross-presenters and drive more prominent CD4+ T cell responses against exogenous antigens. The discovery of the X-C motif chemokine receptor 1 (XCR1) as a specific marker of cross-presenting DCs, has led to the identification of a divergent subset of CD8+ DCs that lacks the ability to cross-present. Here, we report that these poorly characterized CD8+XCR1neg DCs have a gene expression profile that is consistent with both plasmacytoid DCs (pDCs) and cDC2. Our data demonstrate that CD8+XCR1neg DCs possess a unique pattern of endocytic receptors and a restricted toll-like receptor (TLR) profile that is particularly enriched for TLR5, giving them a unique position within the DC immunosurveillance network.