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Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment.

Shibuya KC, Goel VK, Xiong W, Sham JG, Pollack SM, Leahy AM, Whiting SH, Yeh MM, Yee C, Riddell SR, Pillarisetty VG - PLoS ONE (2014)

Bottom Line: Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ.CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood.Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors.

View Article: PubMed Central - PubMed

Affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

ABSTRACT

Objective: The immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA.

Design: We used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients' peripheral blood.

Results: In contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg.

Conclusion: Our data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival.

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Multimodal neoadjuvant therapy alters the regulatory cell makeup of the tumor microenvironment.A) Kaplan-Meier survival of patients in this study. There was a trend towards longer survival among patients undergoing neoadjuvant therapy (p = 0.07). B) Quantification of CD11b+ (p = 0.04) and CD3+cells in neoadjuvant therapy vs. untreated tumors. C) CD4+ cells were unchanged, however CD8+ cells were less frequent after neoadjuvant therapy (p = 0.04). D) Quantification of FOXP3+ cells in treated and untreated tumors (p = 0.002). E) Analysis of ratio of CD8+ to FOXP3+ T cells (p = 0.01) and CD4+ to FOXP3+ T cells (p = 0.01) in treated and untreated tumors.
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pone-0096565-g006: Multimodal neoadjuvant therapy alters the regulatory cell makeup of the tumor microenvironment.A) Kaplan-Meier survival of patients in this study. There was a trend towards longer survival among patients undergoing neoadjuvant therapy (p = 0.07). B) Quantification of CD11b+ (p = 0.04) and CD3+cells in neoadjuvant therapy vs. untreated tumors. C) CD4+ cells were unchanged, however CD8+ cells were less frequent after neoadjuvant therapy (p = 0.04). D) Quantification of FOXP3+ cells in treated and untreated tumors (p = 0.002). E) Analysis of ratio of CD8+ to FOXP3+ T cells (p = 0.01) and CD4+ to FOXP3+ T cells (p = 0.01) in treated and untreated tumors.

Mentions: As shown in Table 1, approximately half of the 40 IHC specimens in this study are from patients who received neoadjuvant therapy consisting of systemic gemcitabine-based chemotherapy plus chemoradiotherapy (n = 19), or chemotherapy alone (n = 2). Neoadjuvant therapy has previously been shown to alter immune populations in peripheral blood of patients with PDA, leading to transient changes in DC subtypes, total T cell population as well as memory cells[33] and a significant reduction in Treg.[34] Since the neoadjuvant treated patients in our study had a trend towards better overall survival than did patients who underwent primary surgical resection (p = 0.07; Figure 6A), we hypothesized that there would be associated differences in the immune infiltrate. We found significantly fewer myeloid cells infiltrating tumors from patients who had received neoadjuvant therapy compared to those who underwent primary surgery (p = 0.04), however there was no difference in numbers of infiltrating CD3+ T cells (Figure 6B). Treated tumors had a somewhat lower average number of CD8+ cells than did untreated ones (p = 0.04), while there was no difference in the number of CD4+ cells (Figure 6C). Importantly, there was significantly less infiltration of treated tumors with FOXP3+ cells (p = 0.002; Figure 6D). Accordingly, the CD8:Treg and CD4:Treg ratios were higher in treated tumors (p = 0.01; Figure 6E), suggesting that preoperative therapy may specifically deplete immunosuppressive cell types in the PDA tumor microenvironment.


Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment.

Shibuya KC, Goel VK, Xiong W, Sham JG, Pollack SM, Leahy AM, Whiting SH, Yeh MM, Yee C, Riddell SR, Pillarisetty VG - PLoS ONE (2014)

Multimodal neoadjuvant therapy alters the regulatory cell makeup of the tumor microenvironment.A) Kaplan-Meier survival of patients in this study. There was a trend towards longer survival among patients undergoing neoadjuvant therapy (p = 0.07). B) Quantification of CD11b+ (p = 0.04) and CD3+cells in neoadjuvant therapy vs. untreated tumors. C) CD4+ cells were unchanged, however CD8+ cells were less frequent after neoadjuvant therapy (p = 0.04). D) Quantification of FOXP3+ cells in treated and untreated tumors (p = 0.002). E) Analysis of ratio of CD8+ to FOXP3+ T cells (p = 0.01) and CD4+ to FOXP3+ T cells (p = 0.01) in treated and untreated tumors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008589&req=5

pone-0096565-g006: Multimodal neoadjuvant therapy alters the regulatory cell makeup of the tumor microenvironment.A) Kaplan-Meier survival of patients in this study. There was a trend towards longer survival among patients undergoing neoadjuvant therapy (p = 0.07). B) Quantification of CD11b+ (p = 0.04) and CD3+cells in neoadjuvant therapy vs. untreated tumors. C) CD4+ cells were unchanged, however CD8+ cells were less frequent after neoadjuvant therapy (p = 0.04). D) Quantification of FOXP3+ cells in treated and untreated tumors (p = 0.002). E) Analysis of ratio of CD8+ to FOXP3+ T cells (p = 0.01) and CD4+ to FOXP3+ T cells (p = 0.01) in treated and untreated tumors.
Mentions: As shown in Table 1, approximately half of the 40 IHC specimens in this study are from patients who received neoadjuvant therapy consisting of systemic gemcitabine-based chemotherapy plus chemoradiotherapy (n = 19), or chemotherapy alone (n = 2). Neoadjuvant therapy has previously been shown to alter immune populations in peripheral blood of patients with PDA, leading to transient changes in DC subtypes, total T cell population as well as memory cells[33] and a significant reduction in Treg.[34] Since the neoadjuvant treated patients in our study had a trend towards better overall survival than did patients who underwent primary surgical resection (p = 0.07; Figure 6A), we hypothesized that there would be associated differences in the immune infiltrate. We found significantly fewer myeloid cells infiltrating tumors from patients who had received neoadjuvant therapy compared to those who underwent primary surgery (p = 0.04), however there was no difference in numbers of infiltrating CD3+ T cells (Figure 6B). Treated tumors had a somewhat lower average number of CD8+ cells than did untreated ones (p = 0.04), while there was no difference in the number of CD4+ cells (Figure 6C). Importantly, there was significantly less infiltration of treated tumors with FOXP3+ cells (p = 0.002; Figure 6D). Accordingly, the CD8:Treg and CD4:Treg ratios were higher in treated tumors (p = 0.01; Figure 6E), suggesting that preoperative therapy may specifically deplete immunosuppressive cell types in the PDA tumor microenvironment.

Bottom Line: Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ.CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood.Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors.

View Article: PubMed Central - PubMed

Affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

ABSTRACT

Objective: The immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA.

Design: We used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients' peripheral blood.

Results: In contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg.

Conclusion: Our data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival.

Show MeSH
Related in: MedlinePlus