CD8+ T Cells That Coexpress RORγt and T-bet Are Functionally Impaired and Expand in Patients with Distal Bile Duct Cancer

Abstract

CD8+ T cells that express retinoic acid–related orphan receptor (ROR)γt (TC17 cells) have been shown to promote procarcinogenic inflammation and contribute to a tolerogenic microenvironment in tumors. We investigated their phenotype and functional properties in relationship to the pathogenesis of human distal bile duct cancer (DBDC). DBDC patients had an elevated level of type 17 immune responses and the frequency of CD8+RORγt+ T cells (TC17 cells) was increased in peripheral blood. The CD8+RORγt+ T cells represented a highly activated subset and produced IL-17A in equal amount as CD4+RORγt+ T cells (TH17 cells). Most CD8+RORγt+ T cells coexpressed T-bet, a lineage transcription factor for TH1 and TC1 development, suggesting that CD8+RORγt+ T cells undergo plasticity toward a TC17/1-like phenotype with coproduction of IL-17A and INF-γ. In comparison with CD8+RORγt− T cells, the CD8+RORγt+ T cells had a higher level of TCR signaling and were terminally differentiated and exhausted. These cells also had impaired ability to re-express perforin after degranulation and reduced cytotoxic immune function. A subset of CD8+RORγt+ T cells expressing a low level of programmed cell death protein 1 and a high level of OX40 were associated with reduced patient survival. In conclusion, CD8+RORγt+ T cells are proinflammatory and functionally impaired and may contribute to the pathogenesis of DBDC.

OX40 and OX40L protein expression of tumor infiltrating lymphocytes in non-small cell lung cancer and its role in clinical outcome and relationships with other immune biomarkers

“…The underlying mechanism was that dectin-1 activate syk, Raf1 and NF-κB signaling that increased p50 and RelB translocation and OX40 expression. In CD8+ T cell signaling, a subset of RORγt+ CD8+ T cells that expressed high-level OX40 was found to be associated with reduced patients (78). Unlike OX40-expressed Treg, the OX40-expressed RORγt+ CD8+ T cells were associated with promoting pro-carcinogenic inflammation and lead to tolerogenic microenvironment in tumors.…”

“…Moreover, as a pivotal biomarker expressed in immune system, OX40 also serves as an important marker in associate with MEK, Dectin-1, RORγt+ CD8+ T Cells and other immune modulator in the anti-cancer immunology setting (76)(77)(78)(79)(80)(81)(82). To our knowledge, the activation of RAS/ MAPK pathway plays an important role in tumor growth and escape, and it is a common phenomenon in clinical cancer settings.…”

Tc17 biology and function: Novel concepts

“…Furthermore, they expressed elevated levels of the inhibitory receptors LAG3 and TIM3. A subset of Tc17 cells expressing PD1 at diminished level (whereas OX40 at high level) were associated with poor survival, suggesting a contribution to pathogenesis in BDBC and existence of heterogeneity within Tc17 cells [14].…”

“…Tc17 cells are present in various gastrointestinal cancers and associate with poor outcome in patients [13,14,79] (Fig. 1).…”

“…They provide protection against viral and bacterial infections and mediate immunity against lethal fungal pneumonia in mouse models [9,11,12]. In gastrointestinal tract-associated cancers IL-17-producing CD8 + T cells associate with poor patient survival [13][14][15], whereas in a mouse melanoma model Tc17 mediate enhanced antitumor immunity [16]. Further studies report on the pathologic contribution of Tc17 cells to autoimmune inflammation including psoriasis [17][18][19] and multiple sclerosis (MS) [20,21] Tc17 cell contribution to protective and pathologic immune responses.…”