Stroma and Immunity

The Stroma & Immunity team led by Hélène Salmon is a junior group established at Icahn School of Medicine at Mount Sinai, New York, and moving to Curie Institute, Paris, in April 2019.

Our lab aims at deciphering the crosstalk between stromal cells, more specifically fibroblasts, and immune cells in peripheral tissues, with a strong focus on cancer lesions.

We are interested in both basic and translational research. Our projects aim at defining the contribution of stromal cells to shaping immune responses against cancer, and deciphering the fundamental mechanisms underlying this regulation. We are particularly fascinated by immune cell dynamics and their tight control by the tissue environment.

Manipulating fibroblasts is a promising avenue to develop new therapeutics against cancer and inflammatory diseases. The ultimate goal is to develop new strategies to target the stromal compartment specifically in tumor lesions and improve tumor responses to current therapies.

Projects

We are using cutting-edge technologies (CITE-seq, single cell-seq, mass cytometry, multiplexed imaging) to provide comprehensive mapping of the stromal cells in solid tumors from cancer patients (lung/bladder cancer) to help understand the biology of tumor-associated stromal cells and their contribution to tumor immunity. Strong collaborations are established between wet-lab researchers and computational biologists.

Image1_HumanExperiments

In addition to human tumor lesions, we also use clinically relevant mouse tumor models to study the stroma-immune crosstalk in cancer. We recently started to investigate cancer-associated fibroblast gene signatures associated with different patterns of T cell infiltration, and aim to identify some of the key fibroblast genes that regulate T cell dynamics in tumors, using CRISPR to knockout candidate genes in a novel ex-vivo tumor/fibroblast spheroid system that we developed.

Beyond cancer, we are also interested in understanding the stromal impact on immune responses in steady state as well as other pathologies, including inflammatory and autoimmune diseases.

Prior work includes:

  1. Developing a technique to monitor T cell migration in human fresh tissue. In this system of fresh tissue slice, fluorescently labeled T cells freshly isolated from the tumor are plated on top of the slice, and imaged in real-time with a wide-field, confocal, or two-photon microscope. Developed in the laboratory of Alain Trautmann and Emmanuel Donnadieu (Cochin Institute, Paris, France), the technique permits for the first time to study cell migration in live human tissue (Salmon et al, Journal of Visualized Experiments 2011. PMID: 21775968).
  2. Discovering novel contributions of the extracellular matrix to regulation of T cell migration in human solid tumors. Using the slice system described above, our previous work shed light on molecular elements controlling T cell distribution and migration within lung tumors, and provided strong evidence for the role of extracellular matrix fibers (through density and orientation) in keeping T cells outside of the tumor cell mass (Salmon et al, Journal of Clinical Investigation 2012. PMID: 22293174).
  3. Identifying key contributors of myeloid cells to antitumor immunity: This work, done in the Miriam Merad lab (Icahn School of Medicine at Mount Sinai, New York) analyzed myeloid cell populations infiltrating melanoma tumors and their contribution to tumor progression and tumor response to immunotherapies. It identified the CD103+ dendritic cells (DCs) as the only immune cell population transporting intact tumor antigen to the lymph node and presenting it to CD8+ antitumor T cells and established that the low number and the low activation state of tumor-associated CD103+ DCs limit the ability of anti-PD-L1 antibodies to induce antitumor immunity. Expansion and activation of these DCs in situ enhances tumor response to checkpoint inhibition therapy (Salmon et al, Immunity 2016. PMID: 27096321). Another project identified some of the mechanisms by which Langerhans cells modulate tumor response to ionized radiation (Price et al, Nature Immunology 2015. PMID: 26343536).

Key publications

Year of publication 2018

Li Wang, Abdel Saci, Peter M Szabo, Scott D Chasalow, Mireia Castillo-Martin, Josep Domingo-Domenech, Arlene Siefker-Radtke, Padmanee Sharma, John P Sfakianos, Yixuan Gong, Ana Dominguez-Andres, William K Oh, David Mulholland, Alex Azrilevich, Liangyuan Hu, Carlos Cordon-Cardo, Hélène Salmon, Nina Bhardwaj, Jun Zhu, Matthew D Galsky (2018 Aug 31)

EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer.

Nature communications : 3503 : DOI : 10.1038/s41467-018-05992-x

Year of publication 2017

Brandon Hogstad, Marie-Luise Berres, Rikhia Chakraborty, Jun Tang, Camille Bigenwald, Madhavika Serasinghe, Karen Phaik Har Lim, Howard Lin, Tsz-Kwong Man, Romain Remark, Samantha Baxter, Veronika Kana, Stefan Jordan, Zoi Karoulia, Wing-Hong Kwan, Marylene Leboeuf, Elisa Brandt, Helene Salmon, Kenneth McClain, Poulikos Poulikakos, Jerry Chipuk, Willem J M Mulder, Carl E Allen, Miriam Merad (2017 Dec 22)

RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions.

The Journal of experimental medicine : 319-336 : DOI : 10.1084/jem.20161881

Year of publication 2016

Hélène Salmon, Juliana Idoyaga, Adeeb Rahman, Marylène Leboeuf, Romain Remark, Stefan Jordan, Maria Casanova-Acebes, Makhzuna Khudoynazarova, Judith Agudo, Navpreet Tung, Svetoslav Chakarov, Christina Rivera, Brandon Hogstad, Marcus Bosenberg, Daigo Hashimoto, Sacha Gnjatic, Nina Bhardwaj, Anna Karolina Palucka, Brian D Brown, Joshua Brody, Florent Ginhoux, Miriam Merad (2016 Apr 21)

Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition.

Immunity : 924-38 : DOI : 10.1016/j.immuni.2016.03.012

Year of publication 2015

Jeremy G Price, Juliana Idoyaga, Hélène Salmon, Brandon Hogstad, Carolina L Bigarella, Saghi Ghaffari, Marylene Leboeuf, Miriam Merad (2015 Sep 8)

CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation.

Nature immunology : 1060-8 : DOI : 10.1038/ni.3270
Miriam Merad, Hélène Salmon (2015 Jul 17)

Cancer: A dendritic-cell brake on antitumour immunity.

Nature : 294-5 : DOI : 10.1038/523294a

Year of publication 2013

Judith Agudo, Albert Ruzo, Navpreet Tung, Hélène Salmon, Marylène Leboeuf, Daigo Hashimoto, Christian Becker, Lee-Ann Garrett-Sinha, Alessia Baccarini, Miriam Merad, Brian D Brown (2013 Nov 26)

The miR-126-VEGFR2 axis controls the innate response to pathogen-associated nucleic acids.

Nature immunology : 54-62 : DOI : 10.1038/ni.2767