Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy
Prokopi et al. JITC (2021)
Checkpoint blockade helps T cells recognize and attack cancer cells by inhibiting the “off” immune signals, but it is not effective for all melanoma patients. Through a multi-institution collaboration, Prokopi A, Tripp CH, Tummers B, et al. set out to understand the underlying mechanisms and crucial role of dermal dendritic cells (DCs) in a melanoma mouse model.
Migrating conventional DC1 (cDC1) and cDC2 are two major dermal subsets presenting tumor antigens to cytotoxic T cells. Using a previously-published 37-marker mass cytometry panel incorporating surface marker and transcription factors differentially expressed in six unique DC subsets , the researchers observed a gradual loss of the dermal cDC2 with melanoma progression, whereas the cDC1 numbers remained unchanged. Furthermore, they found that boosting DC activation using Flt3L, in combination with polyI:C and anti-CD40 could increase both cDC1 and cDC2 numbers within the tumor and increased migration of cDC2 cells to tumor-draining lymph nodes. Furthermore, it was discovered that boosted cDCs efficiently deliver gp100 tumor-associated antigen to gp100-specific CD8+ T cells. As a result, combining the DC boost with checkpoint blockade antibodies against PD-1 and TIM-3 slowed melanoma growth and extended survival in mice.
This study indicated that responsiveness to checkpoint blockade may benefit from boosting the numbers and function of DCs. It also demonstrated the value of high-dimensional mass cytometry in identifying immune subsets that equip T cell-based immunotherapies with effective anti-tumor cytotoxicity.
Reference citation: Prokopi A, Tripp CH, Tummers B, et al. Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy. Journal for ImmunoTherapy of Cancer. 2021. 9:e000832. doi: 10.1136/jitc-2020-000832
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