Cancer Immunology and Immunotherapies.
The demonstration that immune-mediated mechanisms can lead to the specific elimination of cancer cells have brought immune-based interventions to the forefront of cancer therapeutics in modern oncology. However, it has also become clear that developing tumors can escape immune destruction by many mechanisms resulting in the subversion of immunoregulatory processes and leading to the inactivation of anti-tumor immunity. Correlatively, compelling evidence has indicated that inhibition of these cancer-induced immunosuppressive networks is an important prerequisite to uncover the full potential of immunotherapeutic approaches.
Our group conducts a basic and translational research program in cancer immunology and immunotherapy aimed at deciphering the mechanisms of tumor-induced immunosuppression and investigates approaches to override their negative impact on anti-cancer effector cells. A concomitant and complementary area of investigation centers on the propensity of several subsets of T lymphocytes to undergo reprogramming (the ability to trans-differentiate) into pro- or anti-cancer subsets under the influence of the underlying tumor environment. Immunotherapeutic-based strategies are also being explored.
We are specifically focusing on developing the following main axes:
As key controllers of innate and adaptive immune responses, CD4+ T helper (Th) lymphocytes play an essential role in cancer immunosurveillance. However, evidence has emerged that some subsets of Th cells, such as Th17 and Th9, can exhibit both pro- and anti-tumoral effects. This dichotomy has been attributed to the high plasticity of these cells capable of trans-differentiating into either pro-inflammatory effector or immunosuppressive populations (such as regulatory T lymphocytes, Treg) depending on the environment. In this context, the role of Th17 and Th9 in hosts with established malignancies and their possible therapeutic and prognostic value remain incompletely understood. The fact that Th17, Th9, Treg and their hybrid relatives share common differentiation pathways and cytokine requirements likely explains the plasticity of these different subsets and therefore their versatile function in cancer depending on the cytokine content, with TGFb as a likely master regulator among other factors. These questions are currently under investigation in our laboratory. Concomitantly, we are examining the role of T follicular helper (Tfh) in malignancies, specifically in chronic lymphocytic leukemia.
Although traditionally recognized as important anti-tumor cells playing an essential role in cancer immunosurveillance, gd T lymphocytes have recently been documented for their tumor-promoting activities. By analogy to their ab counterparts, it appears that, under specific conditions, gd T cells can also differentiate into distinct subsets endowed with either pro- or anti-tumoral functions. We are developing projects to characterize gd T cell subsets with pro- or anti-tumor activity, explore the influence of the tumor environment on the plasticity of these cells and evaluate the possibility to reprogram tumor-suppressing gd T lymphocytes into stable anti-tumor effectors.
The expansion of immunosuppressive cells represents a cardinal strategy deployed by cancers to avoid immune-mediated elimination. Besides Treg, cells of myeloid origin such as tumor-infiltrating tolerogenic dendritic cells (TiDC), type 2 macrophages (TAM) and myeloid-derived suppressor cells (MDSC) have drawn intense scrutiny for their tumor-promoting role. The modality of induction, the immuno-inhibitory function, the regulation, the pro-angiogenic/pro-metastatic activity and the therapeutic targeting of these cells are being explored. Because cancer-driven myeloid cell populations produce a variety of cytokines and chemokines which can potentially affect the differentiation, recruitment, proliferation and function of Treg, Th17, Th9, Tfh and gd T cells, deciphering the cross-talks between TiDC, TAM, MDSC and these lymphocyte populations is an essential question that we are currently pursuing.
“Cour des moines”, by Laura Rosenbaum
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- Alizadeh D, Larmonier N. Chemotherapeutic targeting of cancer-induced immunosuppressive cells. Cancer Res. 2014 May 15;74(10):2663-8. doi: 10.1158/0008-5472.CAN-14-0301. Epub 2014 Apr PMID:24778417.
- Parikh F*, Duluc D*, Imai N, Clark A, Misiukiewicz K, Bonomi M, Gupta V, Patsias A, Parides M, Demicco EG, Zhang DY, Kim-Schulze S, Kao J, Gnjatic S, Oh S, Posner MR, SikoraChemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer. Cancer Res. 2014 Dec 15;74(24):7205-16. doi: 10.1158/0008-5472.CAN-14-1913. Epub 2014 Oct 15. PMID:25320012. * Equal contribution.
- Duluc D, Joo H, Ni L, Yin W, Upchurch K, Li D, Xue Y, Klucar P, Zurawski S, Zurawski G, Oh S. Induction and activation of human Th17 by targeting antigens to dendritic cells via dectin-1. J Immunol. 2014 Jun 15;192(12):5776-88. doi: 10.4049/jimmunol.1301661. Epub 2014 May 16. PMID:24835401.
- Joo H, Li D, Dullaers M, Kim TW, Duluc D, Upchurch K, Xue Y, Zurawski S, Le Grand R, Liu YJ, Kuroda M, Zurawski G, Oh S. C-type lectin-like receptor LOX-1 promotes dendritic cell-mediated class-switched B cell responses. Immunity. 2014 Oct 16;41(4):592-604. doi: 10.1016/j.immuni.2014.09.009. Epub 2014 Oct PMID:25308333.
- Duluc D, Gannevat J, Anguiano E, Zurawski S, Carley M, Boreham M, Stecher J, Dullaers M, Banchereau J, Oh S. Functional diversity of human vaginal APC subsets in directing T-cell responses. Mucosal Immunol. 2013 May;6(3):626-38. doi: 10.1038/mi.2012.104. Epub 2012 Nov PMID:23131784.
- Alizadeh D, Trad M, Hanke NT, Larmonier CB, Janikashvili N, Bonnotte B, Katsanis E, Larmonier N. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast Cancer Res. 2014 Jan 1;74(1):104-18. doi:10.1158/0008-5472.CAN-13-1545. Epub 2013 Nov 6. PMID:24197130.
- Alizadeh D, Katsanis E, Larmonier N. The multifaceted role of Th17 lymphocytes and their associated cytokines in cancer. Clin Dev Immunol. 2013;2013:957878. doi: 10.1155/2013/957878. Epub 2013 Dec Review. PMID:24454480.
- Hanke N, Alizadeh D, Katsanis E, Larmonier N. Dendriticcelltumorkillingactivity and itspotential applications in cancer immunotherapy. Crit Rev Immunol. 2013;33(1):1-21. PMID:23510023.
- LaCasse CJ, Janikashvili N, Larmonier CB, Alizadeh D, Hanke N, Kartchner J, Situ E, Centuori S, Har-Noy M, Bonnotte B, Katsanis E, Larmonier N. Th-1 lymphocytes inducedendriticcelltumorkillingactivity by an IFN-γ-dependentmechanism. J Immunol. 2011 Dec 5;187(12):6310-7. doi: 10.4049/jimmunol.1101812. Epub 2011 Nov PMID:22075702.
- Lakomy D, Janikashvili N, Fraszczak J, Trad M, Audia S, Samson M, Ciudad M, Vinit J, Vergely C, Caillot D, Foucher P, Lagrost L, Chouaib S, Katsanis E, Larmonier N*, Bonnotte B*. Cytotoxicdendriticcellsgeneratedfrom cancer patients. J Immunol. 2011 Sep 1;187(5):2775-82. doi: 10.4049/jimmunol.1004146. Epub 2011 Jul PMID:21804019. * share senior authorship.
- Duluc D, Corvaisier M, Blanchard S, Catala L, Descamps P, Gamelin E, Ponsoda S, Delneste Y, Hebbar M, Jeannin P. Interferon-gamma reverses the immunosuppressive and protumoralproperties and prevents the generation of humantumor-associatedInt J Cancer. 2009 Jul 15;125(2):367-73. doi: 10.1002/ijc.24401. PMID: 19378341.
- Duluc D, Delneste Y, Tan F, Moles MP, Grimaud L, Lenoir J, Preisser L, Anegon I, Catala L, Ifrah N, Descamps P, Gamelin E, Gascan H, Hebbar M, Jeannin P. Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. 2007 Dec 15;110(13):4319-30. Epub 2007 Sep 11.PMID:17848619.
Pr. Bernard Bonotte (Université de Bourgogne)
Pr. Blandine Gatta-Cherifi (CHU de Bordeaux)
Dr. Alizadeh Darya (City of Hope California, USA)
Dr. Emmanuel Katsanis (University of Arizona, USA)
Dr. Boris Reizis (New York University, USA)
Dr. Dipyaman Ganguly (CSIR-Indian Institute of Chemical Biology, Kalkuta, India)