T cell biology and engineering

We study T-cell responses against tumor antigens in cancer patients with the aims to advance our knowledge of T-cell mediated protection from human disease and to improve T-cell based therapy in the fight against cancer (ref. 1-4). One focus lies in the development of adoptive cell transfer strategies using engineered T cells (ref. 4- 5).

Deciphering the impact of TCR binding avidity on T cell functional potency in well-defined clinical situations.

The efficiency of a T cell response critically depends on how well a T-cell receptor (TCR) binds to a stimulating peptide-MHC (pMHC) complex (also defined as TCR binding avidity). Using the novel developed NTAmer technology, we recently demonstrated that TCR-pMHC binding avidity accurately predicted T cell functional potency of anti-cancer and virus-specific T cell responses in melanoma patients and healthy donors (ref. 1). NTAmer also allows isolating rare, high avidity T cells from patients for their potential use in adoptive T cell therapies (ref. 4; Figure 1). Moreover, we could address which therapeutic vaccine protocol triggered the most potent tumor-specific T cell responses within comparative cohorts of vaccinated patients (ref. 3). Together, the TCR-pMHC binding avidity represents an ideal candidate as a biomarker of T cell therapeutic efficacy and a correlate of T cell immune protection (ref. 1).

Optimization of TCR-ligand binding avidity for cognate tumor antigens.

We investigate approaches to optimize the TCRs with the aim to increase their affinity for cognate tumor antigens (Figure 2). We generated tumor-specific T lymphocytes expressing sequence-optimized TCRs and showed that T cell responses against cancer cells could be specifically improved. However, we found an unexpected functional attenuation of T cells expressing very high affinity TCRs, related to the presence of inhibitory regulators such as the inhibitor receptor PD1 or the SHP1 and SHP2 phosphatases, restricting T cell activation and signaling (ref. 5, unpublished data). Understanding the mechanisms of T cell regulation related to the increased TCR-ligand binding avidity and identifying optimized tumor antigen-specific TCRs directly contributes to the rational development of adoptive cell therapy. 

• Allard M, Couturaud B, Carretero-Iglesia L, Duong MN, Schmidt J, Monnot G, Romero P, Speiser DE, Hebeisen M, and Rufer N. TCR-ligand dissociation rate is a robust and stable biomarker of CD8 T cell potency. JCI Insight. 2017, in press
• Gannon P, Baumgaertner P, Huber A, Iancu EM, Cagnon L, Abed-Maillard S, Maby-El Hajjami H, Speiser DE, and Rufer N. Rapid and continued T cell differentiation into long-term effector and memory stem cells in vaccinated melanoma patients. Clin Cancer Res. CCR-16-1708. 2017, in press
• Gannon PO, Wieckowski S, Baumgaertner P, Hebeisen M, Allard M, Speiser DE and Rufer N. Quantitative TCR:pMHC dissociation rate assessment by NTAmers reveals antimelanoma T cell repertoires enriced for high functional competence. J Immunol. 195(1):356-66. 2015
• Hebeisen M, Schmidt J, Guillaume P, Baumgaertner P, Speiser DE, Luescher I, and Rufer N. Identification of rare high avidity tumor reactive CD8 T cells by monomeric TCR-ligand off-rate measurements on living cells. Cancer Res. 75(10):1983-91. 2015
• Hebeisen M, Baitsch L, Presotto D, Baumgaertner P, Romero P, Michielin O, Speiser DE, and Rufer N. SHP-1 phosphatase activity counteracts increased T cell receptor affinity. J Clin Invest. 123(3):1044-56. 2013

• Swiss National Science Foundation
• ISREC Foundation
• MEDIC Foundation
• Promedica Stiftung