Inflammation & Cancer

My laboratory explores the mechanisms of the innate immune system in cancer progression, anti-tumor immunity and cancer immunotherapy. In parallel, we study the (dys)regulation of innate immunity in chronic inflammatory diseases (CIDs) and the immune related adverse events ellicited by cancer immunotherapies.

Cancer control is intricately linked to the potency of the immune response. The fundamental understanding of cancer-immune cells crosstalk has resulted in breakthroughs in cancer immunotherapies e.g. by immune checkpoint inhibitors (ICI), among others. This has infused energy in oncoimmunology research & development, particularly in two major areas: 1) understanding the mechanisms of efficacy and toxicity of cancer immunotherapies; and 2) harnessing additional mechanisms to boost innate and adaptive anti-tumor immunity. In that realm, our group investigates innate immunity-microbiome-cancer interactions and the role of metabolic pathways in this crosstalk.

Our long-term objectives are to:

1) Dissect the interactomes, synergy or redundancy, and effector functions of innate immunity in cancer and CIDs.

2) Elucidate the metabolic regulation of inflammation and innate immunity.

3) Study the role of the environment-host interactions, the functional microbiome and its cross-regulation by innate immunity pathways in cancer and CIDs.

4) Identify immunological, metabolic and microbial biomarkers underlying patients differential response to immunotherapies.

  • 1.1 To characterize the phenotypes and functions of innate immune cells and non-conventional T cells in the response to ICI.

    We will characterize the numbers, phenotypes and functions of myeloid cells, innate lymphocytes and gamma-delta T cells in the blood and tumor of cancer patients receiving ICI by single cell transcriptomics, FACS and IHC.

  • 1.2 To define the role of the inflammasomes in cancer immuno-surveillance and the response to ICI.

    Based on our previous and preliminary results demonstrating a significant inverse correlation between two inflammasomes and human colon cancer progression, we will address a) immunosurveillance mechanisms in colon cancer governed by these two inflammasomes; b) inflammasome role in ICI efficacy in responsive versus non-responsive cancers; and c) inflammasome role in the microbiome-ICI synergy.

  • 2.1 To define the microbiome metabolic activity linked to ICI efficacy, immune-related adverse events (irAEs) and hyper-progressive disease.

    It is currently unclear how the microbiome contributes to ICI responses. We will metatranscriptomics and metabolomics of plasma and stool samples of cancer patients receiving ICI to define microbial and metabolic determinants of ICI efficacy and toxicity. Results will be validated in gnotobiotic mouse models.

  • 2.2 To determine the contribution of the microbiome in the effect of co-medications on ICI efficacy.

    Based on preliminary results from a retrospective study, in collaboration with the FHU ACRONIM, revealing an impact of select co-medications on overall survival and irAEs in a cohort of patients treated with ICI for advanced cancers, we will explore whether these effects are mediated by the microbiome and how.

  • 2.3 To explore the role of “active” metabolites in modulating the phenotypes and functions of innate immune cells and non-conventional T cells.

    We will study the impact of identified ICI-associated “active” metabolites on anti-tumor immunity and the immune phenotypes and activities of innate immune cells in vitro and in vivo.

  • 3.1 To characterize host-microbiome-derived metabolites in specific forms of inflammatory bowel diseases (IBD).

  • 3.2 To investigate the role of a chromosome X-linked metabolic effector in the pathogenesis and sex bias of Systemic Lupus Erythematosus (SLE).

  • 3.3 To examine the role of mitochondrial homeostasis in SLE pathogenesis.

by Marie-Désirée Smith

TEAM

Head : Maya Saleh

> Gaël GALLI
> Julie GIRAUD
> Audrey HEMADOU
> Pauline RIVIERE
> Virginie BAYLOT (starting in january 2020)
> Eloïse TUDELA (CIFRE with LNC Therapeutics, starting in january 2020)

PUBLICATIONS

Main Publications (last 10 years)

Peer-Reviewed Journals

Rodrigue-Gervais, I. G., Doiron, K., Champagne, C., Mayes, L., Leiva-Torres, G. A., Vanié, P. Jr, Douglas, T., Vidal, S. M., Alnemri, E. S., Saleh M. The mitochondrial protease HtrA2 restricts the NLRP3 and AIM2 inflammasomes. (2018) Scientific Reports. 8(1): 8446-8457.

*Dagenais, M., *Dupaul-Chicoine, J., *Douglas, T., **Champagne, C., *Morizot, A., Saleh, M. The Interleukin (IL)-1R1 pathway is a critical negative regulator of PyMT-mediated mammary tumorigenesis and pulmonary metastasis. (2017) Oncoimmunology. 6 (3): e1287247.

Diamanti, M. A., Gupta, J., Bennecke, M., De Oliveira, T., Ramakrishnan, M., Braczynski, A. K., Richter, B., Beli, P., Hu, Y., Saleh, M., Mittelbronn, M., Dikic, I., Greten, F. R. IKKα controls ATG16L1 degradation to prevent ER stress during inflammation. (2017) J Exp Med. 214 (2): 423-437.

*Skeldon, A. M., *Morizot, A., *Douglas, T., Santoro, N., Kursawe, R., Kozlitina, J., Caprio, S., Mehal, W. Z., Saleh, M. Caspase-12, but Not Caspase-11, Inhibits Obesity and Insulin Resistance. (2016). The Journal of Immunology. 196 (1): 437-447.

*Dagenais, M., *Dupaul-Chicoine, J., **Champagne, C., *Skeldon, A., *Morizot, A., Saleh, M. A critical role for cellular inhibitor of protein 2 (cIAP2) in colitis-associated colorectal cancer and intestinal homeostasis mediated by the inflammasome and survival pathways. (2016). Mucosal Immunology. 9 (1): 146-158.

*Dupaul-Chicoine, J., Arabzadeh, A., *Dagenais, M., *Douglas, T., **Champagne, C., *Morizot, A., *Rodrigue-Gervais, I. G., Breton, V., Colpitts, S. L., Beauchemin, N., Saleh, M. The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity. (2015). Immunity. 43 (4): 751-763.

*Douglas, T., **Champagne, C., *Morizot, A., Lapointe, J. M., Saleh, M. The Inflammatory Caspases-1 and -11 Mediate the Pathogenesis of Dermatitis in Sharpin-Deficient Mice. (2015). The Journal of Immunology. 195 (5): 2365-2373.

Arabzadeh, A., *Dupaul-Chicoine, J., Breton, V., Haftchenary, S., Yumeen, S., Turbide, C., Saleh, M., McGregor, K., Greenwood, C. M., Akavia, U. D., Blumberg, R. S., Gunning, P. T., Beauchemin, N. Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells. (2015). Gut. pii: gutjnl-2014-308781.

Aries, A., Whitcomb, J., *Shao, W., Komati, H., Saleh, M. and Nemer, M. Caspase-1 cleavage of transcription factor GATA4 and regulation of cardiac cell fate. (2014). Cell Death and Disease. 5: e1566.

*Leblanc, P. M.#, Doggett, T. A.#, Choi, J., Hancock, M. A., Durocher, Y., Frank, F., Nagar, B., Ferguson, T. A.# and Saleh, M.# An Immunogenic Peptide in the A-box of HMGB1 Reverses Apoptosis-Induced Tolerance Through RAGE. (2014) The Journal of Biological Chemistry. 289: 7777-7786 (# Contributed equally). Selected as “paper of the week”.

*Rodrigue-Gervais, I. G.#, *Labbé, K.#, Dagenais, M., *Dupaul-Chicoine, J., **Champagne, C., *Morizot, A., *Skeldon, A., Brincks, E. L., Vidal, S. M., Griffith, T. S. and Saleh, M. Cellular inhibitor of apoptosis protein cIAP2 regulates pulmonary tissue necrosis and host survival to influenza A virus infection. (2014) Cell Host and Microbe. 15(1): 23-35. (# Contributed equally).

Highlighted in:

Cell Host and Microbe. 2014 15(1): 3-6

  1. Marivin, A., Berthelet, J., Cartier, J., Paul, C., Gemble, S. *Morizot, A., Boireau, W., Saleh, M., Bertoglio, J., Solary, E. and Dubrez, L. cIAP1 regulates TNF-mediated cdc42 activation and filopodia formation. (2014). Oncogene. 33(48): 5534-5545.

  1. Caignard G, Leiva-Torres GA, Leney-Greene M, Charbonneau B, Dumaine A, Fodil-Cornu N, Pyzik M, Cingolani P, Schwartzentruber J, *Dupaul-Chicoine J, Guo H, Saleh M, Veillette A, Lathrop M, Blanchette M, Majewski J, Pearson A, Vidal SM. (2013). Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1. PLoS Pathog. 9: e1003637

  1. Meunier, C., Van Der Kraak, L., Turbide, C., Groulx, N., Cingolani, P., Blanchette, M., *Yeretssian, G., Saleh, M., Beauchemin, N. and Gros, P. The Mouse Ccs3 Locus: An Intronic Rearrangement in The Nfkb1 Gene Is Associated with Differential Susceptibility To Carcinogen-Induced Colorectal Cancer. (2013). PLoS One. 8(3): e58733

  1. Bongfen, S. E., *Rodrigue-Gervais, I. G., Berghout, J., Torre, S., Cingolani, P., Wiltshire, S. A., Leiva-Torres, G. A., Letourneau, L., Sladek, R., Blanchette, M., Lathrop, M., Behr, M. A., Gruenheid, S., Vidal, S. M., Saleh, M., Gros, P. (2012). An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria. PLoS One. 7 (2): e31012.

  1. *Labbé, K.#, *McIntire, C. R.#, **Doiron, K., *Leblanc, P. M. and Saleh, M. (2011). Cellular Inhibitors of Apoptosis Proteins cIAP1 and cIAP2 Are Required for Efficient Caspase-1 Activation by the Inflammasome. Immunity. 35: 897-907. (# Contributed equally).

Highlighted in:

Immunity. 2012 36: 155-157

  1. Messaed, C., Akoury, E., Djuric, U., Zeng, J., Saleh, M., Gilbert, L., Seoud, M., Qureshi, S., Slim, R. (2011). NLRP7, a nucleotide oligomerization domain-like receptor protein, is required for normal cytokine secretion and co-localizes with Golgi and the microtubule-organizing center. The Journal of Biological Chemistry. 286: 43313-43323.

  1. Liu, X., Nugoli, M., Laferrière, J., Saleh, S. M., *Rodrigue-Gervais, I. G., Saleh, M., Park, M., Hallett, M. T., Muller, W. J., Giguère, V (2011). Stromal retinoic acid receptor beta promotes mammary gland tumorigenesis. PNAS. 108: 774-779.

  1. *Yeretssian, G., Correa, R. G., **Doiron, K., Fitzgerald, P, Dillon, C. P., Green, D. R., Reed, J. C. and Saleh, M. (2011). Non-apoptotic role of BID in inflammation and immunity. Nature. 474 (7349): 96-99.

  1. Wang, P., Arjona, A., Zhang, Y., Sultana, H., Dai, J., Yang, L., *LeBlanc, P., **Doiron, K., Saleh, M.# and Fikrig# (2010). Caspase-12 controls West Nile virus infection via RIG-I. Nature Immunol. 11 (10): 912-919 (# Contributed equally and are Co-Senior authors).

  1. *Labbé, K., Miu, J.,# *Yeretssian, G.,# Serghides, L., Tam, M., Finney, C. A., Erdman, L. K., **Goulet, M., Kain, K. C., Stevenson, M. M and Saleh, M. (2010). Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-B signaling. The Journal of Immunology. 185 (9): 5495-5502.

  1. Miu, J., Saleh, M. and Stevenson M. M. (2010). Caspase-12 deficiency enhances pro-inflammatory and regulatory cytokine responses but does not protect against lethal Plasmodium yoelii 17XL infection. Parasite Immunology. 32 (11-12): 773-778.

  1. *Dupaul-Chicoine, J#., *Yeretssian, G#., **Doiron, K., Bergstrom, K. S. B., *McIntire, C. R., *LeBlanc, P. M., Meunier, C., Turbide, C., Gros, P., Beauchemin, N., Vallance, B. A. and Saleh, M. (2010). Control of intestinal homeostasis, colitis and colitis-associated colorectal cancer by the inflammatory caspases. Immunity. 32 (3): 367-378. (# Contributed equally).

Highlighted in:

  • Nat Rev Immunol. 2010 May;10(5):293.

Immunity. 2010 Mar 26;32(3):300-2.

Faculty of 1000 Biology (ranked as “Must Read”)

  1. Fortier, A., **Doiron, K., Saleh, M., Grinstein, S. and Gros P (2009). Restriction of Legionella pneumophila replication in macrophages requires concerted action of the transcriptional regulators Irf1 and Irf8 and nod-like receptors Naip5 and Nlrc4. Infection and Immunity. 77 (11): 4794-805.

  1. Bertrand, M., **Doiron, K., *Labbe, K., Korneluk, R., Barker, P. and Saleh, M. (2009). cIAP1 and cIAP2 are required for NOD-mediated innate immunity signaling. Immunity. 30 (6): 789-801.

Highlighted in:

Immunity. 2009 Jun 19;30(6):755-6.

Faculty of 1000 Biology (ranked as “Recommended”)

Invited reviews and book chapters

*Songane, M., *Khair, M., Saleh, M. (2018). An updated view on the functions of caspases in inflammation and immunity. Semin Cell Dev Biol. pii: S1084-9521(17): 30118.

*Dagenais, M. and Saleh, M. Linking cancer-induced Nlrp3 inflammasome activation to efficient NK cell-mediated immunosurveillance. (2016). Oncoimmunology. 5(5):e1129484.

*Dagenais, M., *Douglas, T., Saleh, M. (2014). Role of programmed necrosis and cell death in intestinal inflammation. Current Opin. Gastro. 30(6): 566-575

*Barbé, F. *Douglas, T., Saleh, M. (2014). Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev. 25(6): 681-697

*Skeldon, A. M., Faraj, M., Saleh, M. (2014). Caspases and inflammasomes in metabolic inflammation. Immunol Cell Biol. 92: 304-313

*Zhong, P., *Kinio, A. and Saleh, M. (2013). Functions of NOD-like receptors (NLRs) in human diseases. Frontiers in Immunology. 4: 333-351

*Dupaul-Chicoine, J., *Dagenais, M., Saleh, M. (2013). Crosstalk between the intestinal microbiota and the innate immune system in intestinal homeostasis and inflammatory bowel disease. Inflamm Bowel Dis. 19: 2227-2237.

*Rodrigue-Gervais IG, Saleh M (2013). Caspases and immunity in a deadly grip. Trends Immunol. 34(2): 41-49

*Dupaul-Chicoine, J., Saleh, M (2013). Inflammatory Mediators in Tumorigenesis and Metastasis. Book Chapter. Experimental and Clinical Metastasis. Springer science+Business media, LLC 2012.

*Morizot, A. and Saleh, M. (2012). Non-apoptotic functions of cell death effectors in inflammation and innate immunity. Microbes Infect. 14 (14): 1241-1253.

*Dupaul-Chicoine, J., Saleh, M (2012). A new path to IL-1β production controlled by caspase-8. Nat Immunol. 13 (3): 211-212.

*Skeldon, A. and Saleh, M. (2011). The inflammasomes: molecular effectors of host resistance against bacterial, viral, parasitic, and fungal infections. Frontiers in Cellular and infection Microbiology. 2: 15.

Saleh, M. (2011). The machinery of Nod-like receptors: refining the paths to immunity and cell death. Immunol Rev. 243 (1): 235-246.

*Dagenais, M. #, *Skeldon, A. #, Saleh, M. (2012). The inflammasome: in memory of Dr. Jurg Tschopp. Cell Death Differ. 19 (1): 5-12. (# Contributed equally).

Saleh, M. and Elson, C. O. (2011). Experimental inflammatory bowel disease: insights into the host-microbiota dialogue. Immunity. 34: 293-304.

Saleh, M. and Trinchieri G. (2011). Innate mechanisms of colitis-associated colorectal cancer. Nature Reviews in Immunology. 11 (1): 9-20

Skeldon, A. and Saleh, M. (2011). The inflammasomes: molecular effectors of host resistance against bacterial, viral, parasitic, and fungal infections. Frontiers in Cellular and infection Microbiology. 2:15.

*Dagenais, M.#, *Dupaul-Chicoine, J#. and Saleh, M. (2010). Function of NLRs in immunity and disease. Curr. Opin. Invest. Drugs. 11: 1246-1255 (# Contributed equally).

*Labbé, K. and Saleh, M. (2011). Pyroptosis: A Caspase-1-dependent programmed cell death and a barrier to infection. Book chapter. Inflammasomes: Progress in Inflammation Research.

*Rodrigue-Gervais, I. G. and Saleh, M. (2010). Genetics of NLR-associated disorders: a lesson in the guiding principals of NLR function/regulation. Viewpoint issue on the inflammasome. European Journal of Immunology. 40 (3): 643-648.

*LeBlanc, P. and Saleh, M. (2009). Caspases in inflammation and immunity. Book chapter. Encyclopedia of Life Sciences (ELS) and Wiley-Blackwell press.

Saleh, M. (2009). Host-Pathogen Interactions. Book chapter. Cambridge University Press.

*McIntire, C. R. #, *Yeretssian, G. # and Saleh, M. (2009). Inflammasomes in infection and inflammation. Apoptosis. 14 (4): 522-535. (# Contributed equally).

 

FUNDING