Craig Jurisevic

Lung cancer is associated with decreased expression of perforin, granzyme B and interferon (IFN)-γ by infiltrating lung tissue T cells, natural killer (NK) T-like and NK cells

There is a limited understanding how of lung cancer cells evade cytotoxic attack. Previously, we have shown reduced production of the cytotoxic mediator granzyme B by CD8+ T cells in lung cancer tissue. We hypothesized that lung cancer would be further associated with decreased production of granzyme B, perforin and proinflammatory cytokines by other cytotoxic lymphocytes, natural killer (NK) T‐like and NK cells, and that this would result from soluble mediators released by the cancer cells. Lung cancer and non‐cancer tissue from five patients was identified by experienced pathologists. Tumour necrosis factor (TNF)‐α, interferon (IFN)‐γ, granzyme B and perforin were measured in CD4 and CD8+ T, NK T‐like cells and NK cells by flow cytometry. Correlation between cancer stage and granzyme B was analysed retrospectively for 21 patients. The effects of soluble factors released by lung cancer cells on production of cytotoxic mediators and cytokines was assessed, and the role of prostaglandin E2 (PGE)2/COX investigated using indomethacin inhibition. There were significantly decreased percentages of T, NK T‐like and NK cells expressing perforin, TNF‐α and IFN‐γ in cancer versus non‐cancer tissue, and of CD8+ T cells and CD8+ NK T‐like cells expressing granzyme B (e.g. NK T‐like cells: non‐cancer 30% ± 7 versus cancer 6% ± 2·5). Cancer cells released soluble factors that inhibited granzyme B, perforin and IFN‐γ production that was partially associated with the PGE2/COX2 pathway. Thus, lung cancer is associated with decreased expression of granzyme B, perforin and IFN‐γ by infiltrating T cells, NK T‐like and NK cells, possibly as a result of soluble factors produced by the cancer cells including PGE2. This may be an important immune evasion mechanism.

Increased proteinase inhibitor-9 (PI-9) and reduced granzyme B in lung cancer: Mechanism for immune evasion?

Cytotoxic CD8(+) T-cells mount immune responses to cancer via cytotoxic pathways including granzyme B. Cancer cells are also known to develop immune evasion mechanisms. We hypothesised that lung cancer cells would over-express the granzyme B-inhibitor, proteinase inhibitor-9 (PI-9) and down-regulate granzyme B expression by neighbouring CD8(+) T-cells. We investigated PI-9 expression in lung cancer cell lines, and primary lung cancer cells obtained at curative lung resection from cancer patients with/without chronic obstructive pulmonary disease (COPD). Granzyme B and PI-9 expression was also determined in CD8(+) T-cells from the cancer and non-cancer areas of resected lung tissue and from bronchoalveolar lavage (BAL). We then evaluated the effects of conditioned media from lung cancer cell lines on granzyme B expression and the cytotoxic activity of CD8(+) T-cells. PI-9 was highly expressed in lung cancer cell lines. Increased PI-9 expression was also observed in primary cancer cells vs. epithelial cells from non-cancer tissue or bronchial brushing-derived normal primary large airway epithelial cells. Expression significantly correlated with cancer stage. Significantly reduced granzyme B was noted in CD8(+) T-cells from cancer vs. non-cancer tissue. Granzyme B production by CD8(+) T-cells was reduced in the presence of conditioned media from lung cancer cell lines. Our data suggest that lung cancer cells utilise their increased PI-9 expression to protect from granzyme B-mediated cytotoxicity as an immune evasion mechanism, a function that increases with lung cancer stage.

Right video-assisted thoracoscopy thoracic duct ligation as treatment for a case of chyloptysis

CLINICAL SUMMARY A 71-year-old man presented with ongoing expectoration of milky, foul-tasting sputum, while denying any systemic symptoms. He first presented in 2007 with a type B dissection with an aneurysmal complex. He underwent distal aortic arch repair via a left anterolateral thoracotomy approach with femoral-femoral bypass via percutaneous cannulas. The distal aortic arch was transected and a 26-mm Dacron graft was sutured, with a distal anastomosis formed below the pulmonary hilum to the distal descending thoracic aorta. The left subclavian artery was resected as high as possible, anastomosed to an 18-mm Gelseal (Terumo Cardiovascular Systems Corp, Ann Arbor, Mich) graft that was then attached to the aortic graft. The patient was returned to the operating room postoperatively for evacuation of a hematoma, after which he progressed well and was transferred out of the intensive care unit. On day 14, a progressive left pleural effusion was confirmed on computed tomography and tapped using needle thoracostomy. Biochemistry of the specimen confirmed a diagnosis of chylothorax, with a protein level of 22 g/L, an LD level of 530 U/L, and a triglyceride level of 8.3 mmol/L, meeting the diagnostic criteria determined by the Mayo Clinic (>1.24 mmol/L or 110 mg/dL). After a trial of conservative therapy, including tube thoracostomy drainage and 2 weeks of a medium chaintriglyceride diet with octreotide adjunct, the chyle leak persisted and the patient received surgical intervention via redo thoracotomy.

Pleura, Chest Wall, Lung, and Mediastinum

An objective approach to the surgical palliation of pleural, pulmonary, and mediastinal malignancy with a focus on minimally invasive, low-morbidity techniques