CHEST
Volume 148, Issue 3, September 2015, Pages 711-721
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Original Research
Lung Cancer
Tumor Budding Correlates With the Protumor Immune Microenvironment and Is an Independent Prognostic Factor for Recurrence of Stage I Lung Adenocarcinoma

https://doi.org/10.1378/chest.14-3005Get rights and content

BACKGROUND

Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma.

METHODS

Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and forkhead box P3+ (FoxP3+) lymphocytes, CD68+ macrophages, IL-7 receptor, and IL-12 receptor β2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using the competing risks method.

RESULTS

In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs 12%, P ≤ .001), which was confirmed in the validation cohort (P = .005). Tumor budding stratified the risk of recurrence for acinar-predominant (22% vs 9%, P≤ .001), papillary-predominant (22% vs 13%, P = .045), and solid-predominant (39% vs 19%, P = .022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7 receptor overexpression (P ≤ .001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (hazard ratio, 1.61; P = .008).

CONCLUSIONS

Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with the protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at the invading edge as a biologic driver of tumor aggressiveness.

Section snippets

Patient Clinicopathologic Characteristics

The median age of the 1,038 patients was 69 years (range, 23-96 years). Most patients were women (n = 646), and most had stage IA disease (n = 731). Regarding surgical procedures, 796 patients had undergone lobectomy, and 242 had undergone limited resection (segmentectomy [n = 76] and wedge resection [n = 166]). Only 14 patients (1%) received adjuvant chemotherapy.

During the study period, 14% of patients (n = 144) experienced recurrence (locoregional [n = 44] and distant [n = 100]) and 15% (n =

Discussion

We have demonstrated that, in patients with stage I lung adenocarcinoma, tumor budding was an independent prognostic factor that can be used to further stratify risk of recurrence in patients with stage IA, stage IB, acinar-predominant, papillary-predominant, and solid-predominant tumors. Furthermore, it positively correlated with protumor immune cell infiltration, including regulatory T cells and tumor-associated macrophages.

In an attempt to identify prognostic factors for intermediate-grade

Conclusions

In conclusion, we have demonstrated that tumor budding was an independent, unfavorable prognostic factor for disease recurrence in patients with resected stage I lung adenocarcinoma. Moreover, tumor budding positively correlated with protumor immune markers—stromal FoxP3+ lymphocyte infiltration, stromal FoxP3/CD3 lymphocyte index, and tumoral IL-7R expression—and tumor-associated macrophage infiltration. These observations may warrant investigations into interactions between FoxP3+ regulatory

Acknowledgments

Author contributions: W. D. T. and P. S. A. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. K. K., W. D. T., and P. S. A. contributed to study design, data acquisition, analysis, and interpretation; Y.-C. Y., J. V.-V., L. C., and D. R. J. contributed to data acquisition, analysis, and interpretation; E. N. D. and C. S. S. contributed to data analysis and interpretation; and K. K., Y.-C. Y., J. V.-V., L.

References (46)

  • K Koga et al.

    Association of c-Met phosphorylation with micropapillary pattern and small cluster invasion in pT1-size lung adenocarcinoma

    Lung Cancer

    (2013)
  • S Su et al.

    A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis

    Cancer Cell

    (2014)
  • CY Liu et al.

    M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway

    Lab Invest

    (2013)
  • K Kadota et al.

    A grading system combining architectural features and mitotic count predicts recurrence in stage I lung adenocarcinoma

    Mod Pathol

    (2012)
  • K Kadota et al.

    The cribriform pattern identifies a subset of acinar predominant tumors with poor prognosis in patients with stage I lung adenocarcinoma: a conceptual proposal to classify cribriform predominant tumors as a distinct histologic subtype

    Mod Pathol

    (2014)
  • K Kadota et al.

    A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma

    Mod Pathol

    (2012)
  • SS Devesa et al.

    International lung cancer trends by histologic type: male:female differences diminishing and adenocarcinoma rates rising

    Int J Cancer

    (2005)
  • DR Lewis et al.

    US lung cancer trends by histologic type

    Cancer

    (2014)
  • National Lung Screening Trial Research Team et al.

    Reduced lung-cancer mortality with low-dose computed tomographic screening

    NEngl JMed

    (2011)
  • National Lung Screening Trial Research Team et al.

    The National Lung Screening Trial: overview and study design

    Radiology

    (2011)
  • CA van Iersel et al.

    Risk-based selection from the general population in a screening trial: selection criteria, recruitment and power for the Dutch-Belgian randomised lung cancer multi-slice CT screening trial (NELSON)

    Int J Cancer

    (2007)
  • A Warth et al.

    The novel histologic International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification system of lung adenocarcinoma is a stage-independent predictor of survival

    J Clin Oncol

    (2012)
  • R Kalluri et al.

    The basics of epithelial-mesenchymal transition

    J Clin Invest

    (2009)
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    originally published Online First April 2, 2015.

    Preliminary data from this study were presented at the World Conference on Lung Cancer, October 27-31, 2013, Sydney, NSW, Australia.

    FUNDING/SUPPORT: This work was supported by grants from the National Institutes of Health [R21 CA164568-01A1, R21 CA164585-01A1, R01 CA136705-06, U54 CA137788, P50 CA086438-13, and P30 CA008748], the US Department of Defense [PR101053 and LC110202], Mr William H. Goodwin and Mrs Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center.

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