γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Abstract

Summary Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely-activated γδT cell population which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1-polarization of αβT cells. Whereas αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor-protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4+ and CD8+ T cell infiltration and immunogenicity and induced tumor-protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice

“…As elegantly indicated in a recent review (58), murine models using human cells have shortcomings, such as harboring impaired immune infiltrates (e.g., lymphocytes, natural killer cells). This is particularly important, as a complex relationship exists between the immune system and pancreatic cancer development, and these complex interactions have important implications for disease progression and control (59,60). For example, CD8 + T cells and Th1-polarized CD4 + T cells mediate tumor protection in murine pancreatic cancer models and are associated with prolonged survival in humans (61,62).…”

Updates and Critical Evaluation on Novel Biomarkers for the Malignant Progression of Intraductal Papillary Mucinous Neoplasms of the Pancreas

“…Peri-pancreatic lymphocyte subsets have divergent effects on tumorigenesis by either suppressing cancer growth via antigen-restricted tumoricidal immune responses (CD8 + T-cells and Th1-polarized CD4 + T-cells) or by promoting tumor progression via induction of immune suppression (myeloid-derived suppressor cells; MDSCs and Th2-deviated CD4 + T-cells) (76,77). Another study showed that pancreatic adenocarcinoma-infiltrating γδ-T cells are a highly influential lymphocyte subset promoting pancreatic oncogenesis and reducing survival via novel cross-talk with the adaptive immune compartment; Nevertheless, they may also have prognostic significance of survival and response to immunotherapeutic regimen (77). Investigators from our Institution have reported an association between tumorassociated neutrophils (TANs) and advanced IPMN lesions (78).…”

Immunosuppressive γδ T cells foster pancreatic carcinogenesis

“…13 Along similar lines, gd T cells abundantly infiltrated mouse PDAs generated by the orthotopic implantation of malignant cells from Pdx1 Cre ;Kras G12D ;Tp53 R172H (KPC) mice (which spontaneously develop invasive PDAs by 8 weeks of age) into syngeneic immunocompetent hosts. In this system, gd T cells exhibited a peculiar phenotype (as compared to splenic gd T cells), as they were characterized by the upregulation of FAS ligand (FASLG), killer cell lectin-like receptor subfamily B member 1C (KLRB1C, best known as NK1.1), ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, best known as CD39), junction adhesion molecule like (JAML), and TNF receptor superfamily member 4 (TNFRSF4, best known as OX40), as well as by enriched FOXP3…”

“…Similar observations were obtained in 6-month-old Ptf1a Cre ;Kras G12D (KC) mice, a model of preinvasive PDA. 13 Of note, KPC-derived cells orthotopically implanted into Ccr2 ¡/¡ , Ccr5 ¡/¡ , or Ccr6 ¡/¡ mice recruited limited amounts of gd T cells as compared to KPC-derived PDAs established in wild-type (WT) mice, demonstrating the importance of chemokine signaling in this setting. 13 To test whether gd T cells would play an etiologic role in pancreatic carcinogenesis, Daley and collaborators crossed KC mice with Tcrd ¡/¡ mice (which lack gd T cells but contain normal amounts of ab T lymphocytes).…”

“…11,12 Recent data from George Miller's laboratory (from New York University School of Medicine, New York, US) lend further support to this notion as they demonstrate that gd T cells foster pancreatic carcinogenesis by engaging immunological checkpoints on ab T cells. 13 Daley and collaborators observed that gd T cells are virtually absent from the normal human pancreas but account for up to 75% CD3 C T lymphocytes infiltrating human pancreatic ductal adenocarcinomas (PDAs). gd T cells outnumbered CD8…”