Radiotherapy promotes the recruitment and activation of intra-tumoural DCs and enhances CD64+CCR7+ cDC2 egress to the draining lymph node — ASN Events
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Radiotherapy promotes the recruitment and activation of intra-tumoural DCs and enhances CD64+CCR7+ cDC2 egress to the draining lymph node (#245)

Christopher Jones 1 , David Withers 2 , Eleanor Clancy-Thompson 3 , Mark Travis 4 , Tim Illidge 5 , Jamie Honeychurch 5 , Kaye Williams 1
  1. Division of Pharmacy and Optometry, University of Manchester, Manchester, United Kingdom
  2. Centre for Immuno-oncology, University of Oxford, University of Oxford, Oxford, United Kingdom
  3. Early Oncology R&D, AstraZeneca, AstraZeneca, Gaithersberg, Maryland, United States of America
  4. Lydia Becker Institute of Immunology and Infection, University of Manchester, Manchester, United Kingdom
  5. Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom

Dendritic cells (DCs) play a key role in initiating post radiotherapy (RT) immune responses via the uptake and presentation of antigen. However, the dynamics and role of DC subsets involved in post-RT immune responses remains under-explored.

To investigate the impact of RT on DCs we used photoconvertible Kaede mouse models. Kaede mice express a fluorescent protein that switches from green to red following UV exposure (Photoconversion), enabling tracking of immune cell migration from tumours to the draining lymph node (dLN). Subcutaneous MC38 tumours were treated with a 7Gy dose of RT with photoconversion of the tumour 48-hours post treatment. Tumours and LNs were harvested 24-hours or 72-hours after photoconversion with analysis of DCs using flow cytometry.

RT resulted in a reduction of tumour retained (Red) cDC1s (XCR1+) and cDC2s (CD11b+) alongside the increased recruitment of newly infiltrating (Green) cDC2s. The newly infiltrating populations displayed upregulation of activation markers (CCR7, CD40, PD-L2 and CD86). RT also promoted the egress of CD64+CCR7+cDC2s to the dLN which was associated with enhanced CD8+T-cell activation (CD44+CD69+) in the node. The CD64+cDC2s displayed upregulated IRF8, CD86 and PD-L1 expression compared to CD64-cDC2s. Furthermore, the CD64+DCs exhibited increased antigen-MHCI complex expression compared to the CD64- subtype.

IFN-I signalling drives the development of the CD64+cDC2 egressing populations. Blockade of IFNAR-1 did not significantly decrease activated cDC2 numbers but reduced the proportion of egressing cDC2s that acquired the CD64+ phenotype with no significant impact on cDC1-populations. Selective loss of the egressing CD64+DCs was associated with a reduction of CD8+T-cell activation in the dLN.

These findings show that RT can lead to immune stimulation via DC activation alongside IFN-I driven programming of migratory cDC2 populations. This provides insight into the mechanisms associated with post RT responses and supports a role for cDC2s in enhancing CD8+ T-cell responses.