Cancer is one of the diseases that causes the highest number of deaths worldwide.

Until a few years ago, conventional treatment was based on surgery (removal of the tumour) combined with the administration of radiotherapy and/or chemotherapy, in the case of advanced tumours with metastatic spread.

These treatments are quite aggressive and are characterised by high toxicity and low specificity.

In this context of great limitations to address the effective treatment of cancer, immunotherapy contemplates the possibility of using our body's natural defenses that help against infections, to redirect them and put them at the service of the specific defense against to cancer.

The incorporation of CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing technology to our laboratory has allowed the targeted inactivation of gene expression.

The Cas9 protein is used by bacteria as a defense mechanism against infections by bacteriophage viruses and acts as a molecular scissors that can be used to introduce genetic modifications into the cells of interest.

To do this, a guide RNA is used that directs these “molecular scissors” to the exact place in the genome where we want the Cas9 nuclease to cut a given gene.

When the cell tries to repair this damage, it produces errors in the sequence that cause a mutation in the gene of interest and its inactivation. 

In addition to introducing mutations, the technology can be directed to carry out gene therapy and correct defective genes, so, with these molecular scissors, we can carry out gene therapy for diseases with a known genetic basis.

Tumours, as they progress and due to the instability of their genetic material, mutate and generate new proteins that our body can identify as foreign, which triggers an immune response against the tumour.

These innovative therapies, whose effectiveness was initially tested in melanoma with metastasis, have been extended to other types of tumours with similar results.

This implies that it is a global treatment applicable to all types of tumours, specific and selective since our immune system can distinguish normal cells from tumour cells, respecting the former and attacking tumour cells with precision.

Among the tumours that are currently treated with this adjuvant therapy to previously existing ones, include lung, bladder, kidney, breast cancer, skin carcinomas, liver cancer, lymphomas, leukaemias, and there are also currently ongoing clinical trials for practically the entire tumour spectrum.

A high frequency of mutations affecting the gene encoding Herpes Virus Entry Mediator (HVEM, TNFRSF14) is a common clinical finding in a wide variety of human tumours, including those of hematological origin.

In this manuscript, a CRISPR/Cas9 strategy was adopted to abrogate HVEM expression in A20 leukaemia cells.

We have demonstrated that HVEM behaves predominantly as a co-inhibitory receptor since the genetic inactivation of HVEM expression on tumour cells enhances T cell infiltration and improves tumour control.

These results suggest that the PD-1- T cell subpopulation is likely to be a more relevant contributor to tumour rejection than the PD-1+ T cell subpopulation.

These findings highlight the role of co-inhibitory signals delivered by HVEM upon engagement of BTLA on T cells and NK cells, placing HVEM/BTLA interaction in the spotlight as a novel immune checkpoint for the reinforcement of the anti-tumour responses in malignancies of hematopoietic origin.

Cancer is one of the diseases that causes the highest number of deaths worldwide.

Until a few years ago, conventional treatment was based on surgery (removal of the tumour) combined with the administration of radiotherapy and/or chemotherapy, in the case of advanced tumours with metastatic spread.

These treatments are quite aggressive and are characterised by high toxicity and low specificity.

In this context of great limitations to address the effective treatment of cancer, immunotherapy contemplates the possibility of using our body's natural defenses that help against infections, to redirect them and put them at the service of the specific defense against to cancer.

The incorporation of CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing technology to our laboratory has allowed the targeted inactivation of gene expression.

The Cas9 protein is used by bacteria as a defense mechanism against infections by bacteriophage viruses and acts as a molecular scissors that can be used to introduce genetic modifications into the cells of interest.

To do this, a guide RNA is used that directs these “molecular scissors” to the exact place in the genome where we want the Cas9 nuclease to cut a given gene.

When the cell tries to repair this damage, it produces errors in the sequence that cause a mutation in the gene of interest and its inactivation. 

In addition to introducing mutations, the technology can be directed to carry out gene therapy and correct defective genes, so, with these molecular scissors, we can carry out gene therapy for diseases with a known genetic basis.

Tumours, as they progress and due to the instability of their genetic material, mutate and generate new proteins that our body can identify as foreign, which triggers an immune response against the tumour.

These innovative therapies, whose effectiveness was initially tested in melanoma with metastasis, have been extended to other types of tumours with similar results.

This implies that it is a global treatment applicable to all types of tumours, specific and selective since our immune system can distinguish normal cells from tumour cells, respecting the former and attacking tumour cells with precision.

Among the tumours that are currently treated with this adjuvant therapy to previously existing ones, include lung, bladder, kidney, breast cancer, skin carcinomas, liver cancer, lymphomas, leukaemias, and there are also currently ongoing clinical trials. for practically the entire tumour spectrum.

A high frequency of mutations affecting the gene encoding Herpes Virus Entry Mediator (HVEM, TNFRSF14) is a common clinical finding in a wide variety of human tumours, including those of hematological origin. In this manuscript, a CRISPR/Cas9 strategy was adopted to abrogate HVEM expression in A20 leukaemia cells.

We have demonstrated that HVEM behaves predominantly as a co-inhibitory receptor since the genetic inactivation of HVEM expression on tumour cells enhances T cell infiltration and improves tumour control.

These results suggest that the PD-1- T cell subpopulation is likely to be a more relevant contributor to tumour rejection than the PD-1+ T cell subpopulation.

These findings highlight the role of co-inhibitory signals delivered by HVEM upon engagement of BTLA on T cells and NK cells, placing HVEM/BTLA interaction in the spotlight as a novel immune checkpoint for the reinforcement of the anti-tumour responses in malignancies of hematopoietic origin.

Source: Frontiers in Immunology