Antigen-specific T cell repertoires – Cassotta lab

We dissect the human T cell repertoire targeting tumor and self-antigens at the clonal level to elucidate immunodominance and immune tolerance. Learning from nature, we aim to identify therapeutically relevant T cell receptors and epitopes to advance immunotherapies.

Part of the:

Our research

Our mission is to dissect the human T cell repertoire to improve patients’ lives by identifying biomarkers and designing novel immune-based therapies.

In our research, we map human T cell clones targeting tumor and self-antigens to elucidate the rules governing immunodominance, immunological memory, and immune tolerance across different human disease contexts, including cancer. Detailed analysis of patients’ T cell repertoires offers us the opportunity to identify therapeutically relevant T cell receptors (TCRs) and epitopes and to leverage them to design new therapeutic approaches.

We have optimized sensitive target-agnostic screening methods for the high-throughput isolation of antigen-specific T cells recognizing naturally processed peptides from patients (Cassotta et al., Nature Medicine 2019; PMID: 31501610), as well as pipelines for in-depth characterization of their TCR sequences, cognate epitopes, and MHC restriction (Low, …, Sallusto*, Cassotta*, Science 2021; PMID: 34006597).

Learning from nature, we aim to unleash the full potential of the immune system to shape the future of immunotherapy.

Open positions

We are always interested in recruiting talented fellows to join our team. Are you interested in our work? Get in touch: antonino.cassotta@ki.se

Publications

Selected publications

All publications from group members

Funding

Grants

  • Swedish Research Council⁠
    1 July 2026 - 30 June 2032
    Multiple myeloma (MM) is a malignancy of plasma cells that is still incurable, highlighting the urgent need for novel therapies. Myeloma cells abundantly produce a monoclonal antibody, the M-protein, whose fragments are presented on MHC molecules and can be targeted by T cells. However, the reasons why the T cell response fails to control MM remain incompletely understood. Here, I aim to leverage my strong expertise in human immunology to dissect myeloma-reactive T cells, identify T cell receptor (TCR) sequences targeting public myeloma antigens, and engineer novel proof-of-concept cytotoxic cell therapies for MM.Combining antigenic stimulation and TCR sequencing, I will dissect the repertoire of myeloma-reactive T cells in patient’s bone marrow and quantify effector and regulatory T cells. I will isolate TCRs targeting public epitopes uniformly and abundantly presented by myeloma cells, including peptides from the immunoglobulin constant regions and mutated driver oncogenes, and restricted by prevalent HLA alleles. To prevent tumor escape by MHC loss, I will engraft myeloma-reactive TCRs into allogeneic natural killer (NK) cells and γδ-T cells, generating dual-targeting cytotoxic cells able to kill myeloma cells by both TCR-mediated and NK receptor-mediated mechanisms. We anticipate that this project will shed light on the mechanisms of myeloma immune evasion and pave the way for novel off-the-freezer adoptive cell therapies resilient to tumor heterogeneity and MHC loss.
  • Dissection of tumor-reactive T cells to develop TCR-based immunotherapies for multiple myeloma
    Swedish Society for Medical Research
    1 March 2026 - 28 February 2030
  • Swedish Research Council
    1 January 2026 - 31 December 2029
    Multiple myeloma (MM) is a malignancy of plasma cells that produce a uniquely rearranged monoclonal antibody, known as M-protein. The failure of the immune system to eliminate malignant plasma cells remains incompletely understood. Despite therapeutic advancements, MM remains incurable due to recurrent relapses, highlighting the urgent need for new treatment strategies. Genome editing technologies enable the development of cell-based immunotherapies with enhanced specificity and efficacy. Here, I will investigate the endogenous T cell response to MM by characterizing the specificity and function of tumor-reactive T cells within the bone marrow microenvironment. In parallel, I will identify T cell receptors (TCRs) targeting tumor antigens, including conserved idiotypic epitopes from M-proteins and recurrently mutated oncogenes, to develop novel TCR-based immunotherapies. Using precise genome editing, I will engineer TCR-transgenic T cells and natural killer (NK) cells to mitigate tumor evasion due to MHC loss. By dissecting the TCR repertoire and specificity of the endogenous T cell response in MM, this study will provide key insights into immune evasion mechanisms and enable new off-the-shelf and multiplexed TCR-based immunotherapies. The knowledge and methodologies generated in this study will not only advance treatment strategies for MM but also inform the design of next-generation precision immunotherapies against other malignancies.

Staff and contact

Group leader

All members of the group

Visiting address

Karolinska Institutet, H7 Medicin / NEO / HERM, Blickagången 16, Huddinge, 14152, Sweden