Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer

Maria Zagorulya; Leon Yim; Duncan M Morgan; Austin Edwards; Elen Torres-Mejia; Noor Momin; Chloe V McCreery; Izabella L Zamora; Brendan L Horton; James G Fox; K Dane Wittrup; J Christopher Love; Stefani Spranger

doi:10.1016/j.immuni.2023.01.010

Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer

Immunity. 2023 Feb 14;56(2):386-405.e10. doi: 10.1016/j.immuni.2023.01.010. Epub 2023 Feb 2.

Authors

Affiliations

¹ Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA.
² Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
³ Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA.
⁴ Biological Imaging Development CoLab, UCSF, San Francisco, CA 94143, USA.
⁵ Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
⁶ Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA.
⁷ Department of Biological Engineering, MIT, Cambridge, MA 02139, USA; Division of Comparative Medicine, MIT, Cambridge, MA 02139, USA.
⁸ Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
⁹ Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
¹⁰ Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. Electronic address: [email protected].

Abstract

Local environmental factors influence CD8⁺ T cell priming in lymph nodes (LNs). Here, we sought to understand how factors unique to the tumor-draining mediastinal LN (mLN) impact CD8⁺ T cell responses toward lung cancer. Type 1 conventional dendritic cells (DC1s) showed a mLN-specific failure to induce robust cytotoxic T cells responses. Using regulatory T (Treg) cell depletion strategies, we found that Treg cells suppressed DC1s in a spatially coordinated manner within tissue-specific microniches within the mLN. Treg cell suppression required MHC II-dependent contact between DC1s and Treg cells. Elevated levels of IFN-γ drove differentiation Treg cells into Th1-like effector Treg cells in the mLN. In patients with cancer, Treg cell Th1 polarization, but not CD8⁺/Treg cell ratios, correlated with poor responses to checkpoint blockade immunotherapy. Thus, IFN-γ in the mLN skews Treg cells to be Th1-like effector Treg cells, driving their close interaction with DC1s and subsequent suppression of cytotoxic T cell responses.

Keywords: T cell dysfunction; T cell priming; Th1-like effector regulatory T cells; anti-tumor immunity; cross-presenting dendritic cells; cytotoxic T cells; interferon-gamma; non-small cell lung cancer; regulatory T cells; tissue-specific immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Humans
Interferon-gamma
Lung Neoplasms*
T-Lymphocytes, Cytotoxic
T-Lymphocytes, Regulatory*

Substances

Interferon-gamma
IFNG protein, human

Grants and funding

R37 CA273819/CA/NCI NIH HHS/United States