Adnane Achour

We will revise methodology of biomolecular NMR to meet new challenges and opportunities of the post AlphaFold2 integrative life-science studies. We develop a task-oriented approach that combines a novel set of selective and spin system optimized NMR experiments with a next-generation signal processing and analysis using deep learning, artificial neural networks, and automation.The new methodology, which we call Focused Spectroscopy (FOSY), deviates from the traditional approach of uniform data sampling and universal broadband experiments. Instead, FOSY “focuses” sensitivity and resolution at a few but the most important spins residing at hotspots of a protein system. In its turn, advent of the deep learning and artificial neural networks will significantly rehaul the NMR toolbox for spectra acquiring, processing, and analysis. The new N-FOSY methodology will be developed, finetuned, and demonstrated on a number of collaboration projects on biomedically important and challenging protein systems including the T-cell receptors and peptide bound major histocompatibility complexes (TCR-pMHC), 44 kDa mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), 57 kDa photosensory module of bacterio-phytochrome, and the 441aa intrinsically disordered protein Tau. The innovative N-FOSY methodology and the novel results afforded by its application in our showcase studies will greatly extend the usability of NMR and enable a broad range of new challenging research lines.

Peptide-based immunotherapy is one of the experimental methods used today to treat cancer. MHC class I molecules (MHC-I) play a major role in the immune system by binding intracellular peptides and presenting them to CD8 T lymphocytes. The elimination of tumors requires a strong response of cytotoxic T cells against tumor-associated antigens (TAA). Because many TAAs are or resemble endogenous proteins, they bind with low affinity to MHC-I and often elicit a weak immunological response. The goal of this work is to study how a new generation of 'superpeptides' that our research group produced using an innovative procedure, with high affinity and binding stability to MHC-I can mimic disease-related peptides with weak immunogenicity and be strongly immunogenic. This will mean great opportunities for the development of new, more powerful T cell-based cancer vaccines. We intend to analyze the structural and dynamic effects of superpeptide modifications on T cell receptor recognition. Our hope is that our studies will allow us to establish a molecular signature, which would facilitate appropriate T cell and/or peptide therapy. We will continue to study the functional effects of such substituted ´superpeptides´ on the CD8-lymphocyte response, focusing on well-established human and mouse cancer models.

MHC class I (MHC-I) molecules play a crucial role in immune surveillance by presenting intracellular peptides to CD8+ T lymphocytes via T cell receptors (TCRs). Recognition of MHC/peptide complexes by TCRs is a critical event in initiation of immune responses toward cancer and viral infections.Financial support from Vetenskapsrådet and Cancerfonden during the last years have allowed us to design a new generation altered peptide ligands that we call super-peptides, that bind with high affinity to MHC-I molecules. Super-peptides are a powerful and unique tool for improving cancer treatment and vaccines against viral infections. Their increased immunogenicity induces T cell responses of a magnitude never before observed, and the induced CD8+ T cells cross-react with original peptides, resulting in enhanced responses towards cancer and viral targets.Here we intend to combine X-ray crystallography and NMR analyses to assess the structural and dynamic bases underlying the effects of modified peptides on recognition by CD8 TCRs. We are in a unique position to perform such studies based on four well-established different peptides and three TCR models. Besides understanding the possible direct or allosteric effects of the peptide modifications on increased TCR recognition of cancer and viral targets, this study would provide novel insights on pathogen-mediated auto-reactivity. The results from these studies could allow to design novel complementary immunotherapies and/or vaccines.

Peptide-based immunotherapy is one of the experimental methods currently used for the treatment of cancer. MHC class I molecules (MHC-I) play a major role in the immune system by binding intracellular peptides and presenting them to CD8 T lymphocytes. The elimination of tumors requires a strong response from cytotoxic T cells to tumor-associated antigens (TAA). Because many TAAs are body-like proteins or similar, they bind with low affinity to MHC-I and often elicit a weak immunological response. We have established a new method that enhances CD8 T cell responses to cancer models. The aim of this work is to study how a new generation of superpeptides, which our research group has developed with a novel approach, with high affinity and binding stability to MHC-I, can mimic disease-related peptides with weak immunogenicity and be highly immunogenic. This will provide great opportunities for the development of new, more powerful T cell-based cancer vaccines. We now intend to transfer this knowledge to human cancer models, as well as to understand the exact metabolic pathways provoked by various peptide modifications. Within the framework of this research period, I would like to 1) prove that super-peptides provoke strong CD8 T cell responses to various cancer models, especially human

2) develop an mRNA vaccine that presents super-peptides for vaccination against cancer

3) Understand the exact metabolic pathways initiated by various types of tumor-associated epitopes and superpeptide versions.

Peptide-based immunotherapy is one of the experimental methods currently used for the treatment of cancer. MHC class I molecules (MHC-I) play a major role in the immune system by binding intracellular peptides and presenting them to CD8 T lymphocytes. The elimination of tumors requires a strong response from cytotoxic T cells to tumor-associated antigens (TAA). Because many TAAs are body-like proteins or similar, they bind with low affinity to MHC-I and often elicit a weak immunological response. The goal of this work is to study how a new generation of "superpeptides" that our research group has developed with a novel approach, with high affinity and binding stability to MHC-I, can mimic disease-related peptides with weak immunogenicity and be highly immunogenic. This will provide great opportunities for the development of new, more powerful T cell-based cancer vaccines. We intend to analyze the structural and functional effects of such substituted "superpeptides" on the CD8 lymphocyte response, focusing on well-established human and mouse cancer models.

Peptide-based immunotherapy is one of the experimental methods currently used for the treatment of cancer. MHC class I molecules (MHC-I) play a major role in the immune system by binding intracellular peptides and presenting them to CD8 T lymphocytes. The elimination of tumors requires a strong response from cytotoxic T cells to tumor-associated antigens (TAA). Because many TAAs are body-like proteins or similar, they bind with low affinity to MHC-I and often elicit a weak immunological response. The goal of this work is to study how a new generation of "superpeptides" that our research group has developed with a novel approach, with high affinity and binding stability to MHC-I, can mimic disease-related peptides with weak immunogenicity and be highly immunogenic. This will provide great opportunities for the development of new, more powerful T cell-based cancer vaccines. We intend to analyze the structural and functional effects of such substituted "superpeptides" on the CD8 lymphocyte response, focusing on well-established human and mouse cancer models.

Peptide-based immunotherapy is one of the experimental methods currently used for the treatment of cancer. MHC class I molecules (MHC-I) play a major role in the immune system by binding intracellular peptides and presenting them to CD8 T lymphocytes. The elimination of tumors requires a strong response from cytotoxic T cells to tumor-associated antigens (TAA). Because many TAAs are body-like proteins or similar, they bind with low affinity to MHC-I and often elicit a weak immunological response. The goal of this work is to study how a new generation of "superpeptides" that our research group has developed with a novel approach, with high affinity and binding stability to MHC-I, can mimic disease-related peptides with weak immunogenicity and be highly immunogenic. This will provide great opportunities for the development of new, more powerful T cell-based cancer vaccines. We intend to analyze the structural and functional effects of such substituted "superpeptides" on the CD8 lymphocyte response, focusing on well-established human and mouse cancer models.

Peptide-based immunotherapy is one of the experimental methods currently used for the treatment of cancer. MHC class I molecules (MHC-I) play a major role in the immune system by binding intracellular peptides and presenting them to CD8 + T lymphocytes. The elimination of tumors requires a strong response from cytotoxic T cells to tumor-associated antigens (TAA). Because many TAAs are body-like proteins or similar, they bind with low affinity to MHC-I and often elicit a weak immunological response. The aim of this work is to develop a new generation of 'superpeptides' with a new approach that our research group has developed. The "superpeptides" will 1) mimic disease-related peptides with weak immunogenicity, 2) be strong immunogenic and 3) have a high affinity and binding stability to MHC-I. This will provide great opportunities for the development of new, more powerful T cell-based cancer vaccines. We intend to analyze the structural and functional effects of such substituted "superpeptides" on the CD8 lymphocyte response, focusing on melanoma and multiple myeloma.