Selected publications

• Human MAIT cells inhibit alloreactive T-cell responses and protect from acute graft-versus-host disease.
  Talvard-Balland N, Lambert M, Chevalier MF, Tourret M, Bohineust A, Milo I, Parietti V, Yvorra T, Socie G, Lantz O, Caillat-Zucman S.
  [under review in JCI Insight]
• Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy.
  Tourret M, Talvard-Balland N, Lambert M, Ben Youssef G, Chevalier MF, Bohineust A, Yvorra T, Morin F, Azarnoush S, Lantz O, Dalle JH, Caillat-Zucman S.
  J Immunother Cancer. 2021 Oct;9(10):e003123.
• Expansion of Circulating CD49b+LAG3+ Type 1 Regulatory T Cells in Human Chronic Graft-Versus-Host Disease.
  Talvard-Balland N, Sutra Del Galy A, Michonneau D, Le Buanec H, Chasset F, Robin M, Peffault de Latour R, Xhaard A, Sicre de Fontbrune F, Parquet N, Duchez S, Schiavon V, Rybojad M, Bergeron-Lafaurie A, Bagot M, Bensussan A, Caillat-Zucman S, Socié G, Bouaziz JD, de Masson A.
  J Invest Dermatol. 2021 Jan;141(1):193-197.e2

Deciphering TIM-3 signaling to enhance anti-leukemia immunity against AML

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the primary curative treatment for patients with acute myeloid leukemia (AML). The therapeutic benefit of allo-HCT relies on a robust T cell-mediated graft-versus-leukemia effect (GVL)¹. However, allo-HCT as treatment for AML has two major limitations: (i) AML tumor relapse, still occurring in around 40% of patients² and (ii) the development of graft-versus-host disease (GVHD). GVHD represents the most common life-threatening complication where donor T cells recognize, target and attack healthy tissues in the recipient^3,4. While relapse after allo-HCT remains a major therapeutic challenge, several immune escape mechanisms involved have been identified, including the overexpression of inhibitory receptor ligands by AML cells, leading to direct inhibition of immune cell function.

TIM-3, first identified as a molecule expressed on interferon-γ producing T cells, has recently emerged as an inhibitory receptor (IR)^5,6, and more broadly, as a marker for T cell dysfunction/exhaustion in cancer⁷, which makes it a promising target for enhancing T cell immunity against AML. Exhaustion is a functional state characterized by a loss of proliferative capacity, decreased cytokine production and reduced cytotoxic activity⁵. In addition, TIM-3 and its ligand Galectin-9 are highly expressed on leukemic stem cells, inducing an autocrine loop that is essential for their self-renewal and AML development⁸.

In this project, I aim to investigate the mechanisms of TIM-3 blockade to overcome immune escape and reinvigorate immune cells to enhance anti-leukemia immunity after allo-HCT in AML.

Aim 1 To study TIM-3 blockade in the allogenic context, including signaling pathway networks (still not fully understood), metabolic status of donor cells or with regard to GVHD development.

Aim 2 To decipher the interaction between oncogene signaling and IR(s) / ligand(s) expression to identify intrinsic resistance or beneficial mutations to TIM-3 blockade, leading to personalized treatment(s) and/or prognostic biomarker(s).

Aim 3 To characterize ICI combinations to overcome potential treatment resistance.

Immune-checkpoint inhibitors monotherapies often lead to the acquisition of Ab resistance (e.g., aberrant cell signaling), inducing tumor relapse and immune-related adverse events (irAEs), resulting in inflammation⁹. Combination treatment with immunotherapies appears to be a favorable strategy to prolong the activation of the immune response, decrease immunosuppression, and target signaling and resistance pathways, leading to a more durable and long-lasting treatment.

References

1. M. M. Horowitz et al. Blood 75, 555-562 (1990).

2. P. Tsirigotis et al. Bone Marrow Transplant 51, 1431-1438 (2016).

3. G. Socie, J. Ritz. Blood 124, 374-384 (2014).

4. R. Zeiser, B. R. Blazar. N Engl J Med 377, 2167-2179 (2017).

5. E. J. Wherry, M. Kurachi. Nat Rev Immunol 15, 486-499 (2015).

6. K. O. Dixon et al. Nature 595, 101-106 (2021).

7. M. Hashimoto et al. Annu Rev Med 69, 301-318 (2018).

8. Y. Kikushige et al. Cell Stem Cell 17, 341-352 (2015).

9. K. L. Reynolds et al. J Immunother Cancer 9, (2021).