In this issue of Blood, Brown et al demonstrate that T cells acquire antigens through intercellular protein transfer from malignant plasma cells rendering them novel regulators of T-cell proliferation.1
Intercellular protein transfer has been recognized as a mode of communication within the immune system for nearly 30 years, yet only with the advent of recent technology has our understanding of how this happens really expanded. One such mechanism of intercellular protein transfer is trogocytosis (from the Greek trogo, meaning gnaw), a process whereby a direct and rapid exchange of membrane fragments between APCs and T cells results in the transfer of immune-modulatory surface proteins. The formation of an immune synapse through cell surface ligand/receptor interaction (MHC-TCR, CD28-B7, CD54-LFA, MHC-I–KIR) facilitates the rapid transfer (within minutes) of cell-surface, transmembrane, and intracellular molecules encompassed in a membrane patch, resulting in a modification of the immune response.2 Research to date (both murine and human) has demonstrated that intercellular transfer is more efficient in activated T cells, underpinning the central role of TCR-MHC engagement in the facilitation of trogocytosis. However, the exact mechanism or mechanisms involved in trogocytosis remain unclear. It may represent the physical disruption of the immune synaptic membrane as cells attempt to dissociate, especially where there is a high avidity ligand/receptor interaction.3
What is the physiologic purpose of trogocytosis? The immune response is the orchestration of multiple cell types with complex specific functions in the pursuit of target eradication, for example, viral infected cells. The effectiveness of the immune response not only rests with recognition of the target with resulting initiation of the response, but the balance between expansion and limitation of such a response to ensure target eradication without overzealous collateral damage. Numerous studies to date have indicated a role for trogocytosis in the evolution of the immune response. The process of intercellular protein transfer can augment the immune response through transfer of stimulatory membrane portions, in particular acquired MHC class II/peptide (MHCIIpacq) and co-stimulatory molecules (“presentasomes”), resulting in the generation of APC-like T cells. Such APC-like T cells can amplify the response through sustained T-cell activation and cytokine production.4 By contrast, trogocytosis can also play a role in regulating the immune response. MHCpacq+ CD4+ T cells have been shown to induce neighboring CD4+ T-cell anergy or apoptosis and CD8+ T cells that have captured cognate MHC class I/peptide complexes can become susceptible to antigen-specific cytolysis by neighboring CD8+ T cells (“fratricide”) resulting in a dampening of the antigen-driven clonal response.
What is the role that intercellular protein transfer plays in limiting the extent of the immune response? It has previously been shown that HLA-G, a nonclassical MHC molecule characterized by strong immunosuppressive function and highly restricted tissue expression under physiologic conditions (mediating immune tolerance at the maternal-fetal interface), can be acquired from APCs by both CD4+ and CD8+ T cells.5 The transfer of HLA-G (along with CD86, CD54, and ILT-3) to primarily activated T cells results in hyporesponsive T cells that acquire regulatory function. As such, trogocytosis provides a mechanistic explanation of how the immune system may regulate the extent of the immune response under physiologic conditions, which was previously assumed to only occur through cytokine-driven lineage commitment of the peripheral immune compartment to generate regulatory T cells.
However, the elegant experimental data presented by Ross and colleagues takes this physiologic cellular process into the realm of the pathologic.1 Although it has been the desire of tumor immunologists to use the host immune system to overcome malignant cells, it is clear from an abundance of research that the tumor cell can avoid/evade immune control. The exact mechanism for this varies for each tumor type. The work by Ross et al demonstrates that the intercellular transfer of HLA-G and CD86 from the tumor cells of myeloma induced T cells with regulatory capacity. This demonstrates for the first time that intercellular protein transfer occurs from tumor cells to T cells rather than from APCs. Furthermore, they demonstrate that these HLA-Gacq+ T cells were more prevalent in the immediate tumor microenvironment (bone marrow) compared with the immune cell compartment of peripheral blood. In addition, the expression of HLA-G and CD86 by myeloma plasma cells was demonstrated to have a prognostic significance, indicative of the relevance of tumor-induced immune suppression in the biology of myeloma.
Is T-cell acquisition of HLA-G and CD86 by trogocytosis the sole mechanism of tumor-induced immune suppression in myeloma? Not likely. The host-immune conflict in myeloma is almost certainly multifactorial, reliant on both cell-contact and soluble factor-mediated immune modulation (see figure). For example, we have shown that CD4+CD25+FoxP3+ TReg cells are increased in the peripheral blood of patients with myeloma relating to the tumor cell burden and that in vitro, myeloma cells mediate TReg-cell induction from uncommitted T0 cells, mediated in part through ICOS (Inducible T-cell COStimulator)/ICSOL interactions.6,7 Nonetheless, the evidence indicates that trogocytosis plays a role in propagating tumor-induced immune suppression in myeloma, although interestingly, the effect is not so prominent in the other mature B-cell malignancies examined (chronic lymphocytic leukemia and Waldenström lymphoma).
The task to overcome this multifaceted tumor-induced immune suppression may seem daunting. However, in recent years the novel agents employed in managing myeloma have, in addition to imposing tumoricidal effects, have the ability to augment the host immune system and, in some reported series, reverse host immune dysfunction.8-10 As such, it may be the multifaceted nature of myeloma-induced immune dysfunction that ultimately proves to be its downfall. Until then, the contribution of well-designed translational work in tumor immunobiology, exemplified by Ross and colleagues, serves us all in the design of novel therapeutic interventions of the future.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■