T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Abstract

Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8 + cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)-and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1 + myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40 and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies. Graphical abstractMarigo et al. show that nitric oxide produced by Tip-DCs, a subset of tumor-infiltrating myeloid cells, is important for tumor control by adoptive cell therapy (ACT). Tip-DCs require the CD40-CD40L pathway but not CSF-1R, CSF-1R blockade reduces immunosuppressive macrophages and improves tumor control by ACT.

T Cells Encountering Myeloid Cells Programmed for Amino Acid-dependent Immunosuppression Use Rictor/mTORC2 Protein for Proliferative Checkpoint Decisions

“…However, a key implication of our work concerns extensions to scenarios where T cell activation is desired in immunosuppressive microenvironments. For example, widely used antibodies that block CTLA4 and the PD1 pathway can rescue T cell growth in immunosuppressive cancer microenvironments where Arg1ϩ macrophages are present, often in large numbers (1,55). An objective of cancer therapy is the combinatorial disabling of the immunosuppressive microenvironment by targeting immune checkpoints and other pathways such as arginases and the tryptophan-metabolizing IDO proteins.…”

Understanding the tumour micro‐environment communication network from an NOS2/COX2 perspective

“…(TIP)‐DC subset was shown to exert a direct role in killing microbes, thereby mediating the innate immune response. A recent study showed that interaction between anti‐tumour CD8 + T‐cells and NO producing Tip‐DCs regulates tumour growth in mouse model (Marigo et al ., ). In contrast, NOS2 in human DCs is yet to be identified.…”

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

“…The oxidation of arginine by NOS produces nitric oxide (NO), which can interact with reactive oxygen species to generate reactive nitrogen species that are toxic for intratumoral T cells (Mocellin et al, 2007). However, local NO production by intratumoral DC can alternatively promote tumor destruction by adoptively transferred CD8 cytotoxic T cells (Marigo et al, 2016), indicating NO can have pro- or anti-tumor activity. High levels of ARG in tumor cells correlate with an increase in suppressive TAMs (Tham et al, 2014).…”