Oncologic Trogocytosis Protects Tumour Stromal Cells from γδ Cell Cytotoxicity

Tumours progressively develop chemoresistance and immunoescape abilities thanks to support from their stromal microenvironment. In ovarian carcinomas, for instance, tumour-associated mesenchymal stem cells （TAMC） can transfer multi-drug-resistant proteins to develop metastases. However, since the microenvironment of such carcinomas is frequently infiltrated by both TAMC and γδ T lymphocytes, the consequences of interactions between these cell types were unclear. Here, we report that whilst γδ T lymphocytes were not activated when co-incubated in vitro with TAMC, their cell membranes were trogocytosed by the TAMC. Since TAMC constitutively express a low level of HLA class I, which is increased by trogocytosis of γδ cell-derived HLA class I, the interaction increased the expression of HLA class-I molecules on TAMC. In addition, γδ T lymphocytes are HLA-unrestricted cytolytic cells and their activity is regulated by inhibitory receptors （KIR） for self-HLA class I. Hence, although the lytic activity of γδ T lymphocytes for unrelated target cells was unaffected by trogocytosis, it spared the TAMC. Therefore, interactions between TAMC and cytolytic γδ T cells avoided the killing of these stromal cells due to an active transfer of their protective HLA class-I molecules. These results suggest that trogocytosis contributes to the maintenance of cancer-associated stromal cells.

What lessons can be learned from y T cell-based cancer immunotherapy trials？

During the last several years, research has produced a significant amount of knowledge concerning the characteristics of human 76 T lymphocytes. Findings regarding the immune functions of these cells, particularly their natural killer cell-like lyric activity against tumor cells, have raised expectations for the therapeutic applications of these cells for cancer. Pharmaceutical companies have produced selective agonists for these lymphocytes, and several teams have launched clinical trials of y8 T cell-based cancer therapies. The findings from these studies include hematological malignancies （follicular lymphoma, multiple myeloma, acute and chronic myeloid leukemia）, as well as solid tumors （renal cell, breast and prostate carcinomas）, consisting of samples from more than 250 patients from Europe, Japan and the United States. The results of these pioneering studies are now available, and this short review summarizes the lessons learned and the role of y6 T cell-based strategies in the current landscape of cancer immunotherapies.

Self-activation of Vγ9Vδ2 T cells by exogenous phosphoantigens involves TCR and butyrophilins

The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not completely known.Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells,such as immune presenting cells or tumor cells.In this study,we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs,involving their TCR and the butyrophilins BTN3A1 and BTN2A1.This is the first time that these three molecules,concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells,have been shown to be involved together on the same and unique T cell during PAg activation.Moreover,the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed byγ9TCR,BTN3A1 and BTN2A1.The self-activation of Vγ9Vδ2 T cells,which leads to self-killing,can therefore participate in the failure ofγδT cell-based therapies with exogenous PAgs and should be taken into account.