TY - JOUR
T1 - Systemic immune activity predicts overall survival in treatment-Naïve patients with metastatic pancreatic cancer
AU - Farren, Matthew R.
AU - Mace, Thomas A.
AU - Geyer, Susan
AU - Mikhail, Sameh
AU - Wu, Christina
AU - Ciombor, Kristen
AU - Tahiri, Sanaa
AU - Ahn, Daniel
AU - Noonan, Anne M.
AU - Villalona-Calero, Miguel
AU - Bekaii-Saab, Tanios
AU - Lesinski, Gregory B.
N1 - Funding Information:
This work was funded in part by the US National Cancer Institute's Cancer Therapy Evaluation Program (Trial number: NCT01280058) and associated Phase II N01 program grant (HHSN261201100070C, PI: M.A. Villalona-Calero), the William Hall Fund for Liver and Pancreatic Cancer Research (PI: T. Bekaii-Saab), and independent grant support from Oncolytics Inc. (PI: T. Bekaii-Saab and G.B. Lesinski). M.R. Farren received salary support from the Pelotonia Research Foundation (Postdoctoral Fellowship) and from an NIH postdoctoral training grant (5 T32 CA 90223-12, PI: William Carson). This work was also supported by the Pelotonia Fellowship Program and an NIH postdoctoral training grant, 5 T32 CA 90223-12.
Publisher Copyright:
©2015 American Association for Cancer Research.
PY - 2016/5/15
Y1 - 2016/5/15
N2 - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate <7% and is ultimately refractory to most treatments. To date, an assessment of immunologic factors relevant to disease has not been comprehensively performed for treatment-naïve patients. We hypothesized that systemic immunologic biomarkers could predict overall survival (OS) in treatment-naïve PDAC patients. Experimental Design: Peripheral blood was collected from 73 patients presenting with previously untreated metastatic PDAC. Extensive immunologic profiling was conducted to assess relationships between OS and the level of soluble plasma biomarkers or detailed immune cell phenotypes as measured by flow cytometry. Results: Higher baseline levels of the immunosuppressive cytokines IL6 and IL10 were strongly associated with poorer OS (P = 0.008 and 0.026, respectively; HR = 1.16 and 1.28, respectively), whereas higher levels of the monocyte chemoattractant MCP-1 were associated with significantly longer OS (P = 0.045; HR = 0.69). Patients with a greater proportion of antigen-experienced T cells (CD45RO+ )hadlongerOS(CD4 P = 0.032; CD8 P = 0.036; HR = 0.36 and 0.61, respectively). Although greater expression of the T-cell checkpoint molecule CTLA-4 on CD8+ T cells was associated with significantly shorter OS (P = 0.020; HR = 1.53), the TIM3 molecule had a positive association with survival when expressed on CD4+ T cells (P = 0.046; HR = 0.62). Conclusions: These data support the hypothesis that baseline immune status predicts PDAC disease course and overall patient survival. To our knowledge, this work represents the largest cohort and most comprehensive immune profiling of treatment-naïve metastatic PDAC patients to date.
AB - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate <7% and is ultimately refractory to most treatments. To date, an assessment of immunologic factors relevant to disease has not been comprehensively performed for treatment-naïve patients. We hypothesized that systemic immunologic biomarkers could predict overall survival (OS) in treatment-naïve PDAC patients. Experimental Design: Peripheral blood was collected from 73 patients presenting with previously untreated metastatic PDAC. Extensive immunologic profiling was conducted to assess relationships between OS and the level of soluble plasma biomarkers or detailed immune cell phenotypes as measured by flow cytometry. Results: Higher baseline levels of the immunosuppressive cytokines IL6 and IL10 were strongly associated with poorer OS (P = 0.008 and 0.026, respectively; HR = 1.16 and 1.28, respectively), whereas higher levels of the monocyte chemoattractant MCP-1 were associated with significantly longer OS (P = 0.045; HR = 0.69). Patients with a greater proportion of antigen-experienced T cells (CD45RO+ )hadlongerOS(CD4 P = 0.032; CD8 P = 0.036; HR = 0.36 and 0.61, respectively). Although greater expression of the T-cell checkpoint molecule CTLA-4 on CD8+ T cells was associated with significantly shorter OS (P = 0.020; HR = 1.53), the TIM3 molecule had a positive association with survival when expressed on CD4+ T cells (P = 0.046; HR = 0.62). Conclusions: These data support the hypothesis that baseline immune status predicts PDAC disease course and overall patient survival. To our knowledge, this work represents the largest cohort and most comprehensive immune profiling of treatment-naïve metastatic PDAC patients to date.
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U2 - 10.1158/1078-0432.CCR-15-1732
DO - 10.1158/1078-0432.CCR-15-1732
M3 - Article
C2 - 26719427
AN - SCOPUS:84968648426
SN - 1078-0432
VL - 22
SP - 2565
EP - 2574
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -