Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition

By Hélène Salmon, J. Idoyaga, Adeeb H. Rahman, M. Leboeuf, R. Remark, Stefan Jordan, M. Casanova-Acebes, Makhzuna N Khudoynazarova, Judith Agudo, Navpreet Tung and 12 more. Immunity, 2016

1,074 citations recorded by the source corpus.

Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103+ dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8+ T cells. CD103+ DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PDL1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the cytokine Flt3L followed by intratumoral poly I:C injections expanded and activated CD103+ DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103+ DCs in tumors limits checkpoint blockade efficacy and Flt3L-poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/f6b3750a1851892bfe6cef90abfdb966d27c004d

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In Immunology

1. Rafi Ahmed
2. Arlene H. Sharpe
3. G. Freeman
4. K. Araki
5. S. Spranger
6. D. Dai
7. B. Horton
8. T. Gajewski

In Oncology

1. Rafi Ahmed
2. Arlene H. Sharpe
3. G. Freeman
4. S. Spranger
5. T. Gajewski
6. Erik Sahai
7. D. Dai
8. B. Horton

Citations in the corpus

• Dysfunctional CD8+ T cells form a proliferative, dynamically regulated compartment within human melanoma (2018, neutral): “The presence of various myeloid cell populations has previously been suggested as a potential modifier of T cell activity in tumors (Binnewies et al., 2018; Lavin et al., 2017; Salmon et al., 2016).”
• Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 (2018, neutral): “(Figure S2C), although previous studies identified CD103 DCs as important cells for immune responses to tumors (Salmon et al., 2016; Spranger et al., 2015; Ruffell et al., 2014; Broz et al., 2014).”
• Rescue of exhausted CD8 T cells by PD-1 targeted therapies is CD28-dependent (2017, background): “Indeed, recent studies found associations between dendritic cell infiltration and maturation and response to PD-1 blockade (22, 23).”
• Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy (2017, background): “This notion is supported by a recent study combining systemic Flt3-ligand injection with intra-tumoral polyI:C in the BPC mouse model (Salmon et al., 2016).”
• Dendritic Cells and Cancer Immunity (2016, background): “This has been convincingly demonstrated using Batf3-deficient mice, as these fail to reject highly immunogenic cancer cell lines [5, 6] and do not respond to checkpoint blockade therapy using antibodies against programmed death 1 (PD-1) [7, 8].”