Background Conventional dendritic cells (cDC) are critical mediators of protective anti-tumor CD8+ T-cell responses.1 Batf3-driven DC1 are the predominant cDC subset driving anti-tumor immunity due to their specialized ability to cross-present antigens for T-cell activation.2–4 However, the contribution of other tumor-infiltrating DC subsets such as CD11b+ DC2 to anti-tumor immunity remains poorly characterized. Recent studies suggest that under inflammation, DC subsets can exist in various functional states with differential impacts on their stimulatory potential.5–7 In this study, we sought to dissect the contributions of distinct DC states during a productive or dysfunctional anti-tumor immune response. A nuanced understanding of DC activation states in tumors and the signals that drive them carries therapeutic potential to modulate anti-tumor immunity and enhance immunotherapy responses.
Methods We compared the DC infiltrate of a regressing tumor and a progressing tumor to study DC states. Flow immunophenotyping and RNA-sequencing was performed to profile the intratumoral DC compartment. Sorted DC subsets were co-cultured with T-cells ex vivo to evaluate their stimulatory capacity. Cross-dressing (in vivo /ex vivo) was assayed by staining for transfer of tumor-derived H-2b MHC complexes to MHC-mismatched or β2M-deficient DC.
Results Anti-tumor CD8+ T-cell responses in Batf3-/- mice lacking DC1 were maintained in regressor tumors but not progressor tumors, suggesting DC1-independent anti-tumor immunity. Functional assays and RNA-sequencing of the intratumoral DC compartment of regressor tumors revealed a Zbtb46-dependent CD11b+ cDC activation state expressing an interferon-stimulated gene signature (ISG+ DC) that was critical for driving optimal anti-tumor CD8+ T-cell responses. Sorted ISG+ DC could activate CD8+ T-cells similar to DC1. Unlike cross-presenting DC1, however, ISG+ DC acquired antigens by cross-dressing with tumor-derived peptide-MHC, thereby bypassing the requirement for cross-presentation to initiate CD8+ T-cell-immunity. Interestingly, ISG+ DC were enriched in regressor tumors compared to progressor tumors, and this was attributable to constitutive tumor cell-intrinsic type-I-interferon (IFN-I) production in regressor tumors. Ablation of tumor cell-derived IFN-I in regressor tumors led to complete loss of anti-tumor T-cell responses in Batf3-/- mice. Conversely, addition of IFNβ to progressor tumors induced ISG+ DC and rescued anti-tumor T-cell responses in Batf3-/- mice.
Conclusions We identified a novel IFN-I-induced activation state of CD11b+ cDC, called ISG+ DC, that was capable of driving anti-tumor CD8+ T cell immunity by cross-dressing with tumor-derived pMHC complexes in the absence of DC1. Engaging additional functional states of DC, such as ISG+ DC, will strengthen anti-tumor immunity and may improve immunotherapy responses.
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