Association of Immunologic Markers With Survival in Upfront Resectable Pancreatic Cancer | Allergy and Clinical Immunology | JAMA Surgery | JAMA Network
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Table 1.  Demographic and Immunohistochemical Features
Demographic and Immunohistochemical Features
Table 2.  Cox Proportional Hazards Regression Analysis and Kaplan-Meier Survival Estimates for Populations With High and Low CD3+ and Peripheral Monocyte Levels
Cox Proportional Hazards Regression Analysis and Kaplan-Meier Survival Estimates for Populations With High and Low CD3+ and Peripheral Monocyte Levels
1.
Clark  CE, Hingorani  SR, Mick  R, Combs  C, Tuveson  DA, Vonderheide  RH.  Dynamics of the immune reaction to pancreatic cancer from inception to invasion.  Cancer Res. 2007;67(19):9518-9527.PubMedGoogle ScholarCrossref
2.
Carstens  JL, Correa de Sampaio  P, Yang  D,  et al.  Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer.  Nat Commun. 2017;8:15095.PubMedGoogle ScholarCrossref
3.
Inman  KS, Francis  AA, Murray  NR.  Complex role for the immune system in initiation and progression of pancreatic cancer.  World J Gastroenterol. 2014;20(32):11160-11181.PubMedGoogle ScholarCrossref
4.
Hiller  JG, Perry  NJ, Poulogiannis  G, Riedel  B, Sloan  EK.  Perioperative events influence cancer recurrence risk after surgery.  Nat Rev Clin Oncol. 2018;15(4):205-218.PubMedGoogle Scholar
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    Research Letter
    November 2018

    Association of Immunologic Markers With Survival in Upfront Resectable Pancreatic Cancer

    Author Affiliations
    • 1Liver and Pancreatic Surgery Program, Providence Portland Cancer Center, Portland, Oregon
    • 2Division of Gastrointestinal and Minimally Invasive Surgery, The Oregon Clinic, Portland
    • 3Integrated Therapies Laboratory, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon
    JAMA Surg. 2018;153(11):1055-1057. doi:10.1001/jamasurg.2018.1757

    Pancreatic ductal adenocarcinoma (PDAC) is typically infiltrated by immune cells that influence the response to conventional therapies.1,2 In addition, growing tumors cause systemic immune dysregulation, including expansion of myeloid populations.3 Finally, recovery from surgery results in a systemic wound healing response that can perturb peripheral immune populations.4 We hypothesized that peripheral expansion of myeloid or T cells would reflect similar increases in the tumor microenvironment and that increased intratumoral T-cell levels and robust postoperative immune recovery would correlate with improved outcome.

    Methods

    We conducted a prospective cohort study of resectable PDAC to determine which immunologic variables are associated with improved prognosis. We restricted our analysis to adult patients (18-100 years of age) who underwent upfront resection for PDAC from June 14, 2010, to November 24, 2014. We excluded patients who received neoadjuvant therapy, had other histologic subtypes, or had palliative surgery only. Peripheral populations were quantified in blood drawn before incision on the day of surgery and on the first postoperative visit with quantitative flow cytometry. We evaluated levels of CD3+, CD8+, CD8+/CD25+, CD4+, CD4+/CD25+, monocytes, CD14+ monocytes, and total granulocytes. Tumor-infiltrating immune cells were quantified by immunohistochemistry and quantitative digital image analysis for CD3+, CD68+, and CD8+ cells, as well as percentage of cells staining positive for programmed cell death ligand 1. Data were analyzed from November 6, 2011, through August 16, 2017. The primary outcome was overall survival. Secondary outcomes were correlation between peripheral circulating blood populations and tumor immune infiltrates. Significance is indicated by P < .05. This study was approved by the institutional review board of Providence Portland Cancer Center, Portland, Oregon, and all patients provided written informed consent.

    Results

    We recruited 63 patients (36 men [57%] and 27 women [43%]; median [interquartile range] age, 67 years [49-87 years]). Demographic characteristics and survival of these patients are outlined in Table 1. Clinicopathologic variables were evaluated for association with survival outcomes (Table 2). Median (interquartile range) overall survival was 19.7 months (12.8-35.8 months) from the time of surgery. Preoperative analysis of peripheral blood populations was complete for 50 patients. Analysis by Cox proportional hazards regression did not reveal any association with survival (Table 2), although higher preoperative monocyte levels trended toward decreased overall survival. Regression analysis did not reveal any association between peripheral blood populations and the presence of intratumoral CD3+, CD8+, or CD68+. Immunohistochemical analysis of tumor infiltrate was completed for 53 patients and revealed a positive association between CD3+ infiltrate and overall survival (hazard ratio, 0.27; 95% CI, 0.07-0.96; P = .04) but not with survival for CD68+ or CD8+ cells.

    Postoperative peripheral blood analysis was complete for a total of 41 patients. Of these, only increasing monocyte count was associated with improved outcome (Table 2), with improved survival found with increasing CD4+ cell levels. Patients were also divided into groups with high (n = 26) and low (n = 27) levels of CD3+ using median expression as a cutoff. Median survival was 20.5 and 18.8 months, respectively, and the 5-year survival estimate was 18.0 months (95% CI, 6.0-35.1 months) and 5.56 months (95% CI, 0.5-2.6 months), respectively. A similar analysis was performed for those with high (n = 22) and low (n = 22) levels of postoperative circulating monocytes. Median survival was 25.3 and 21.6 months, respectively; 5-year estimate of survival, 21.3 months (95% CI, 4.7-45.9 months) and 9.5 months (95% CI, 0.9-31.1 months), respectively.

    Multivariate Cox proportional hazards regression was performed using clinicopathologic and immunohistochemical information. Initially, all variables significant on the univariate analysis were included, and subsequently nonsignificant variables were removed in a stepwise fashion until the final model was generated. American Joint Committee on Cancer stage, CD3+ tumor infiltrate, lymphovascular invasion, and postoperative circulating monocytes remained significant (Table 2).

    Discussion

    Only a subgroup of patients with pancreatic cancer present with malignant neoplasms that are eligible for surgical resection, and these are skewed toward early-stage disease. Within our study population and within the immune cell types studied, preoperative analysis of peripheral lymphocytes was not associated with survival and was not reflective of the intratumoral immune infiltrate. However, higher levels of tumor-infiltrating CD3+ T cells and higher postoperative circulating levels of monocytes were associated with an improved prognosis. These data suggest that, although peripheral blood immunocytes do not reflect the immune environment of the tumor, consideration of the systemic immune response during recovery from resection may be of value. Our data suggest a possible role for the patient’s immune response on the outcome of pancreatic tumor resection and that interventions that change the tumor immune environment and the systemic response in the postresection period could influence patient outcomes.

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    Article Information

    Accepted for Publication: April 22, 2018.

    Corresponding Author: Michael J. Gough, PhD, Integrated Therapies Laboratory, Earle A. Chiles Research Institute, Providence Portland Medical Center, 4805 NE Glisan St, Ste 2N35, Portland, OR 97213 (michael.gough@providence.org).

    Published Online: August 8, 2018. doi:10.1001/jamasurg.2018.1757

    Author Contributions: Drs Gough and Tang had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Tang, Newell, Hansen, Gough.

    Acquisition, analysis, or interpretation of data: Tang, Newell, Wolf, Cottam, Ballestros-Merino, Gough.

    Drafting of the manuscript: Tang, Ballestros-Merino, Gough.

    Critical revision of the manuscript for important intellectual content: Tang, Newell, Wolf, Hansen, Cottam, Gough.

    Statistical analysis: Tang.

    Obtained funding: Hansen, Gough.

    Administrative, technical, or material support: Tang, Hansen, Cottam, Gough.

    Supervision: Newell, Hansen, Gough.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This study was supported by research scholar grant RSG-12-168-01-LIB from the American Cancer Society and the Providence Opportunity Fund.

    Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: Marka Crittenden, MD, PhD, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon, assisted in the design and execution of these studies. This contribution was not compensated.

    References
    1.
    Clark  CE, Hingorani  SR, Mick  R, Combs  C, Tuveson  DA, Vonderheide  RH.  Dynamics of the immune reaction to pancreatic cancer from inception to invasion.  Cancer Res. 2007;67(19):9518-9527.PubMedGoogle ScholarCrossref
    2.
    Carstens  JL, Correa de Sampaio  P, Yang  D,  et al.  Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer.  Nat Commun. 2017;8:15095.PubMedGoogle ScholarCrossref
    3.
    Inman  KS, Francis  AA, Murray  NR.  Complex role for the immune system in initiation and progression of pancreatic cancer.  World J Gastroenterol. 2014;20(32):11160-11181.PubMedGoogle ScholarCrossref
    4.
    Hiller  JG, Perry  NJ, Poulogiannis  G, Riedel  B, Sloan  EK.  Perioperative events influence cancer recurrence risk after surgery.  Nat Rev Clin Oncol. 2018;15(4):205-218.PubMedGoogle Scholar
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