“Helper” immune cells may attack the trick used by cancer to hide

By losing the signals that help them escape CD8+ T lymphocytes, some tumor cells may expose an unexpected vulnerability to CD4+ T lymphocytes

A discovery by researchers at the University of Michigan and Baylor College of Medicine in the USA suggests that cancer cells that escape the surveillance of the immune system may, after all, become vulnerable to another type of body defense: lymphocytes T CD4+seen as “helper” cells.

recently published in Nature Immunology, challenges decades of research in immunology and may have future implications for the development of cancer immunotherapies and the study of transplant-associated diseases.

At the heart of the investigation is a mechanism used by tumor cells to avoid being detected.

These cells can reduce or hide your “identification cards” molecular, known as “major histocompatibility complex”or MHC.

The loss of MHC class I helps them escape to CD8 T lymphocytes+, cytotoxic immune cells that normally recognize and destroy infected or abnormal cells.

Until now, the dominant view was that MHC I was mainly associated with the action of CD8+ T lymphocytes, while MHC class II guided the response of CD4+ T lymphocytes.

MHC I molecules are expressed by practically all nucleated cells, with the exception of red blood cellsand serve to inform the immune system about the status of the cell.

MHC II appears mainly on cells of the immune system that present antigens, such as macrophagesand alerts T lymphocytes to potentially harmful material in the body.

The new results, obtained in experimental mice and validated in genetic databases of treatments carried out on human patients, indicate that cancer cells that no longer display MHC I markers can continue to be attacked by CD4+ T lymphocytes.

“Although pathogens and tumor cells often reduce MHC I-mediated antigen presentation to escape immune surveillance, our observations now suggest that this deficiency may, paradoxically, make them sensitive to elimination mediated by CD4+ T lymphocytes”, write the authors.

Second Pavan Reddyimmunologist at Baylor College of Medicine and lead author of the study, the work, if confirmed by additional studies, could have implications “beyond cancer and transplant immunology“.

The team also studied models of “graft-versus-host disease“, a complication in which stem cells transplanted from a donor attack healthy tissue in the recipient.

In these models, even without MHC I markers, CD4+ T lymphocytes managed to destroy target intestinal cellshelping to explain how donor immune cells can damage the intestine.

The researchers also identified the mechanism used in these cases: the ferroptosean iron-dependent form of programmed cell death.

According to the authors, ferroptosis contributes to the severity of the disease of the graft versus the gastrointestinal host, although it remains to be determined whether it also participates in injuries to other organs.

The discovery is recent and needs confirmation, mainly because the main research was carried out in mice. Even so, can pave the way to new strategies targeting MHC class I and CD4+ T lymphocytes, both to reinforce useful immune responses and to reduce unwanted responses.

The authors argue that it will be necessary to delve deeper into the biological mechanisms in clinical studies and understand whether this joint work between T lymphocytes applies to different types of cancer.