Interleukin-2 immunotherapy action on innate immunity cells in peripheral blood and tumoral tissue of pancreatic adenocarcinoma patients

Degrate, Luca; Nobili, Cinzia; Franciosi, Chiara; Caprotti, Roberto; Brivio, Fernando; Romano, Fabrizio; Leone, Biagio Eugenio; Trezzi, Rosangela; Uggeri, Franco

doi:10.1007/s00423-008-0393-4

Cited by 22 publications

(15 citation statements)

References 42 publications

(53 reference statements)

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“…70 In addition to cellular therapy, IL-2 was also applied (SC 12 Â 10 6 IU) for 3 days before surgery to prevent immune suppression associated with surgery and anesthesia to reduce tumor spread. 71,72 In summary, we have been able to show that we can reliably expand pancreatic cancer TILs that show a Th1 profile. Individual TIL lines recognized commonly shared TAAs and autologous tumor cells.…”

Section: Discussionmentioning

confidence: 94%

Expansion of Tumor-reactive T Cells From Patients With Pancreatic Cancer

Meng

Liu

Rangelova

et al. 2016

Journal of Immunotherapy

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Generation of T lymphocytes with reactivity against cancer is a prerequisite for effective adoptive cellular therapies. We established a protocol for tumor-infiltrating lymphocytes (TILs) from patients with pancreatic ductal adenocarcinoma. Tumor samples from 17 pancreatic cancer specimens were cultured with cytokines (IL-2, IL-15, and IL-21) to expand TILs. After 10 days of culture, TILs were stimulated with an anti-CD3 antibody (OKT3) and irradiated allogeneic peripheral blood mononuclear cells. Reactivity of TILs against tumor-associated antigens (mesothelin, survivin, or NY-ESO-1) was detected by intracellular cytokine production by flow cytometry. Cytotoxicity was measured using a Chromium 51 release assay, and reactivity of TILs against autologous tumor cells was detected by INF-[gamma] production (ELISA). TIL composition was tested by CD45RA, CCR7, 4-1BB, LAG-3, PD-1, TIM3, and CTLA-4 marker analysis. TCR V[beta] was determined by flow cytometry and TCR clonality was gauged measuring the CDR3 region length by PCR analysis and subsequent sequencing. We could reliably obtain TILs from 17/17 patients with a majority of CD8(+) T cells. CD3(+)CD8(+), CD3(+)CD4(+), and CD3(+)CD4(-)CD8(-)[double-negative (DN) T cells] resided predominantly in central (CD45RA(-)CCR7(+)) and effector (CD45RA-CCR7-) memory subsets. CD8(+) TILs tested uniformly positive for LAG-3 (about 100%), whereas CD4(+) TILs showed only up to 12% LAG-3(+) staining and PD-1 showed a broad expression pattern in TILs from different patients. TILs from individual patients recognized strongly (up to 11.9% and 8.2% in CD8(+)) NY-ESO-1, determined by ICS, or mesothelin, determined respectively by TNF-[alpha] and IFN-[gamma] production. Twelve of 17 of CD8(+) TILs showed preferential expansion of certain TCR V[beta] families (eg, 99.2% V[beta]13.2 in CD8(+) TILs, 77% in the V[beta]1, 65.9% in the V[beta]22, and 63.3% in the V[beta]14 family). TCR CDR3 analysis exhibited monoclonal or oligoclonal TCRs, some of them (eg, CD8(+) V[beta]13.2) reacting strongly against autologous tumor defined by INF-[gamma] production or by cytotoxicity. We have optimized methods for generating pancreatic cancer–specific TILs that can be used for adoptive cellular therapy of patients with pancreatic cancer.

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Section: Discussionmentioning

confidence: 94%

Expansion of Tumor-reactive T Cells From Patients With Pancreatic Cancer

Meng

Liu

Rangelova

et al. 2016

Journal of Immunotherapy

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“…In particular, studies on the infiltration of lymphocytes into the tumour have been actively conducted from a pathological perspective . Regarding the correlation between immunologic function and oncologic outcome, increasing numbers of tumour antigen‐specific CD8+ T lymphocytes and natural killer cells are associated with better prognosis in PDAC . On the basis of these studies, attempts have been made to apply immunological methods to patient treatment .…”

Section: Discussionmentioning

confidence: 99%

Association of preoperative total lymphocyte count with prognosis in resected left‐sided pancreatic cancer

Rho

Hwang

Chong

et al. 2019

ANZ Journal of Surgery

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Background: Immunologic factors such as neutrophil-lymphocyte ratio and platelet-lymphocyte ratio play an important role in predicting the oncologic outcome of patients in pancreatic ductal adenocarcinoma (PDAC). It is hypothesized that host immunity represented by total lymphocyte count at diagnostic stage would influence oncologic outcome in left-sided PDAC. Methods: Between January 1992 and August 2017, total of 112 patients who underwent distal pancreatectomy for left-sided PDAC were included and analysed. Results: At the time of the diagnosis, total lymphocyte count at diagnosis of left-sided PDAC was 1.8 AE 0.7 10 3 /μL (mean value AE standard deviation). Among different cut-off values, 1.7 showed most powerful significant differences in long-term oncologic outcomes. The patients with preoperative lymphocyte count (≤1.7) was associated with early recurrence (median 8.4 months versus 18.1 months, P = 0.011) and shorter survival (median 18.6 months versus 35.9 months, P = 0.028). Patients with preoperative total lymphocyte count over 1.7 showed higher white blood cell count (P < 0.001), platelet count (P = 0.039), neutrophil count (P = 0.004) and monocyte count (P = 0.001). However, more interestingly, neutrophil-lymphocyte ratio (P < 0.001) and platelet-lymphocyte ratio (P < 0.001) were found to be significantly higher in those with total lymphocyte count less than 1.7. Lymphocyte to monocyte ratio was inversely related to preoperative total lymphocyte count (P < 0.001). Only age was identified to be significantly different (P = 0.007). However, other clinicopathological parameters generally known to be related to tumour aggressiveness, were not different between two groups. Conclusion: In conclusion, preoperative total lymphocyte at diagnostic stage is simple, and good prognostic factor in left-sided pancreatic cancer.

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“…In contrast to other inflammatory cells, increasing numbers of tumor antigen-specific CD8 + T and natural killer cells are associated with better prognosis 87, 88 . However, even if immune effector cells are present in PDAs, they are not functional or are poorly cytotoxic.…”

Section: Innate and Adaptive Immune Cells In Pda Developmentmentioning

confidence: 99%

Role of Immune Cells and Immune-Based Therapies in Pancreatitis and Pancreatic Ductal Adenocarcinoma

et al. 2013

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Immune cells are important in pathogenesis of acute pancreatitis (AP) and determine disease severity. Results from cytokine-based clinical trials for AP have been disappointing, so strategies that target and alter the behavior of infiltrating immune cells require consideration. Recurrent AP can progress to chronic pancreatitis (CP). CP is a well-described risk factor for pancreatic ductal adenocarcinoma (PDA). However, most patients with CP do not develop PDA, and most patients with PDA do not have history of pancreatitis. Interestingly, CP and PDA tissues have similarities in their desmoplasia and inflammatory infiltrates, indicating overlapping inflammatory responses. Further studies are needed to determine the differences and similarities of these responses, improve our understanding of PDA pathogenesis, and develop specific immune-based therapies. Immune cells in PDA produce immunosuppressive signals that allow tumors to evade the immune response. Unlike single therapeutic agent studies that block immunosuppressive mechanisms, studies of combination therapies that include therapeutic vaccines have provided promising results.

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Interleukin-2 immunotherapy action on innate immunity cells in peripheral blood and tumoral tissue of pancreatic adenocarcinoma patients

Cited by 22 publications

References 42 publications

Expansion of Tumor-reactive T Cells From Patients With Pancreatic Cancer

Expansion of Tumor-reactive T Cells From Patients With Pancreatic Cancer

Association of preoperative total lymphocyte count with prognosis in resected left‐sided pancreatic cancer

Role of Immune Cells and Immune-Based Therapies in Pancreatitis and Pancreatic Ductal Adenocarcinoma

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