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Nathalie RUFER Department of oncology UNIL CHUV |
Phone +41 21 692 59 77 |
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Research interest
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Funding
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Nathalie RUFER Department of oncology UNIL CHUV |
Phone +41 21 692 59 77 |
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).
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).
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as the inhibitor receptor PD1 or the SHP1 and SHP2 phosphatases, restricting T cell activation and signaling (ref. 5, unpublished data).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.