Research Topic

Cancer cell therapy using non-MHC-restricted T cells

About this Research Topic

Tumor cell therapy represents one of the major breakthroughs in modern translational medicine. The possibility to redirect T cells against cancer cells in a specific manner has changed the therapeutic approaches to several tumors. However, important limitations have become apparent which currently constrain use of these approaches mostly against haematological malignancies. A major approach is transfer of TCR genes in recipient T cells to redirect their TCR-mediated antigen recognition. While this approach has the important advantage of targeting peptide neoantigens preferentially or uniquely generated in tumor cells, its major caveat is that it is limited by HLA-polymorphism. Furthermore, the strongest tumor neoantigens derived from cancer DNA mutations are mostly unique to each patient. These features still make this therapeutic approach very cumbersome, slow and costly, given the need to isolate TCRs recognizing any given HLA-tumor peptide complexes.



The goal of this collection is to present and discuss the important aspects of tumor cell therapy using non-MHC-restricted T cells, collectively defined “unconventional” as opposed to the MHC-restricted “conventional” ones. The important implications, possible benefits and strategies to optimize the use of such unconventional T cells should provide a synthetic, but still detailed view of how these T cells might impact cancer immunotherapy. Our goal is also to examine the pitfalls, current difficulties and limitations of using non-conventional T cells. In particular, the difficulties represented by current partial knowledge of the mechanisms of antigen recognition, the nature of immunogenic molecules and the side effects linked to recognition of healthy cells together with cancer cells will be addressed.



The scope of the collection is to assemble together reviews illustrating all the unconventional T cell populations in humans, including T cells restricted to CD1 molecules, to MR1 and T cells expressing the TCR γδ. Each of these cell populations is characterized by unique biological features that require a dedicated discussion of current knowledge and required future studies. We would also like to get the interest of scientists involved in dissecting the basic biological mechanisms to be exploited and make tumor cells optimal targets of unconventional T cells. Descriptions of the rules of selection, tolerance induction and maturation into effector and exhausted cells will be solicited as well, and we hope they will be discussed for each T cell population. Finally, we would like to include clinically-oriented reviews that may discuss the available data and outcomes of completed trials.


Keywords: Cancer therapy, Cell therapy, TCR therapy, CD1, MR1, TCR gamma delta therapy


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Tumor cell therapy represents one of the major breakthroughs in modern translational medicine. The possibility to redirect T cells against cancer cells in a specific manner has changed the therapeutic approaches to several tumors. However, important limitations have become apparent which currently constrain use of these approaches mostly against haematological malignancies. A major approach is transfer of TCR genes in recipient T cells to redirect their TCR-mediated antigen recognition. While this approach has the important advantage of targeting peptide neoantigens preferentially or uniquely generated in tumor cells, its major caveat is that it is limited by HLA-polymorphism. Furthermore, the strongest tumor neoantigens derived from cancer DNA mutations are mostly unique to each patient. These features still make this therapeutic approach very cumbersome, slow and costly, given the need to isolate TCRs recognizing any given HLA-tumor peptide complexes.



The goal of this collection is to present and discuss the important aspects of tumor cell therapy using non-MHC-restricted T cells, collectively defined “unconventional” as opposed to the MHC-restricted “conventional” ones. The important implications, possible benefits and strategies to optimize the use of such unconventional T cells should provide a synthetic, but still detailed view of how these T cells might impact cancer immunotherapy. Our goal is also to examine the pitfalls, current difficulties and limitations of using non-conventional T cells. In particular, the difficulties represented by current partial knowledge of the mechanisms of antigen recognition, the nature of immunogenic molecules and the side effects linked to recognition of healthy cells together with cancer cells will be addressed.



The scope of the collection is to assemble together reviews illustrating all the unconventional T cell populations in humans, including T cells restricted to CD1 molecules, to MR1 and T cells expressing the TCR γδ. Each of these cell populations is characterized by unique biological features that require a dedicated discussion of current knowledge and required future studies. We would also like to get the interest of scientists involved in dissecting the basic biological mechanisms to be exploited and make tumor cells optimal targets of unconventional T cells. Descriptions of the rules of selection, tolerance induction and maturation into effector and exhausted cells will be solicited as well, and we hope they will be discussed for each T cell population. Finally, we would like to include clinically-oriented reviews that may discuss the available data and outcomes of completed trials.


Keywords: Cancer therapy, Cell therapy, TCR therapy, CD1, MR1, TCR gamma delta therapy


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

21 November 2021 Abstract
21 March 2022 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

21 November 2021 Abstract
21 March 2022 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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