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Recent FDA approval of anti-PD-1 antibody pembrolizumab as a site-agnostic therapy for mismatch repair (MMR)–deficient solid tumours has highlighted the importance of CD8+ T cell responses and the potential of immunotherapy, even in tumour entities that are traditionally considered poor candidates for immune-based therapies, such as pancreatic carcinoma.1 Clearly, the old dogma of immunologically cold pancreatic carcinoma has to be refined.
It has been known for long that higher levels of intratumoural CD8+ cytotoxic T lymphocytes (CTLs) correlate with better survival of patients with pancreatic carcinoma.2 3 However, in most pancreatic carcinomas, endogenous CD8+ T cells are relatively sparse.4 Moreover, intratumoural macrophages, myeloid-derived suppressor cells and regulatory T cells (Tregs) dominate even the earliest phases of pancreatic cancer development, and predominance of these immunosuppressive cell populations persists through invasive cancer. This immune privilege of pancreatic cancer is characterised by a comparatively low mutational burden resulting in fewer neoantigens as well as early immune suppression resulting in an exclusion of T cells from the core tumour.5
T cells entering a tumour via bloodstream get into contact with stromal cells presenting tumour-specific antigens to the T cells in the context of an immunosuppressive microenvironment.6 In this setting, CD8+ CTLs will transform into a dysfunctional state characterised by upregulation of inhibitory receptors, like TIM-3 and PD-1, resulting in loss of effector function. Checkpoint inhibitors, such as pembrolizumab, revert this dysfunctional state in some tumour entities, such as malignant melanoma. However, clinical trials on checkpoint inhibition in pancreatic carcinoma showed very limited efficacy.7 The key to better efficacy of immunotherapy in all patients with pancreatic carcinoma, not only in subgroups such as MMR-deficient tumours, will be a better understanding of the crosstalk between CD8+ T cells and cells of the stromal compartment that mediate CTL dysfunction.
Here, Goehrig et al describe βig-h3 as a mediator of T cell–suppressive effects of stroma cells in pancreatic cancer.8 A repressive effect of this protein on T-cell activation had been described by the same authors in a type 1 diabetes model recently.9 Mechanistically, βig-h3 repressed diabetogenic T-cell activation by interfering with early factors in the TCR signalling pathway, such as Lck. This is relevant as it might indicate common mechanisms in autoimmunity and cancer of the pancreas.
βig-h3 is an extracellular matrix protein that was first isolated from A549 human lung adenocarcinoma cells that were treated with TGF-β. The name βig-h3 derives from its cloning as TGF-β-induced gene human clone 3.10 βig-h3 has roles in many processes including morphogenesis, migration, angiogenesis, inflammation and wound healing.
In the current paper, Goehrig et al show that βig-h3 is expressed by stromal cells in tumour tissue of developing pancreatic cancer, but not by exocrine compartments of control mice. It is cancer-associated fibroblasts rather than tumour cells that express βig-h3 in genetically engineered mouse models of pancreatic cancer. Increased expression of βig-h3 in pancreatic cancer has been described before; however, Goehrig et al associate βig-h3 expression with reduced CD8+ T-cell function, resulting in higher tumour growth. βig-h3 depletion increases the CD8+ T-cell response in a model using subcutaneous tumour grafts. In the KPC model, abrogation of βig-h3 results in pronounced antitumour effects.
These findings help us to understand how immune cell populations within the tumour stroma transmit activating versus exhausting signals between themselves. Targeting βig-h3 within pancreatic tumours might represent a promising therapeutic approach.
Contributors CAB has drafted and written the manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
Patient consent for publication Not required.
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