Tumor infiltrating lymphocytes in lung cancer: a new prognostic parameter

There has been a long-lasting interest in the role of the immune system in the development, progression and prognosis of cancer. A seemingly straightforward way to investigate the role of the immune system in cancer is to look at the immune infiltration in the tumor. It is indeed known for many years that the microenvironment in the tumor contains natural killer cells, different types of lymphocytes and antigen presenting cells, all of which play a role in the tumor immune response. As early as 2002, the complex role of lymphocytes in cancer growth was becoming clear (1). Tumor lymphocytic infiltration (TLI) and macrophages may both promote or suppress tumor progression. Consequentially, it should not come as a surprise that studies that looked at tumor-infiltrating lymphocytes as a single entity found contradicting results for survival (2-10). Therefore, more biology-driven TIL subsets were studied (11-17). The infiltration in the tumor stroma of CD4+/CD8+ T-cells was the most consistently correlated with survival, with a higher ratio being related to a better survival in surgical patients.

However, larger studies with external validation were lacking and besides the prognostic, also the predictive influence of the TIL infiltration is of great interest. The study of Brambilla et al. (18) should therefore be welcomed. This large international effort in patients with localized non-small cell lung cancer (NSCLC) investigated the effect of intense versus non-intense TLI on overall survival (OS), disease-free survival (DFS) and specific disease-free survival (SDFS). A discovery set (one trial, 824 patients) and a validation set (three trials, 984 patients) of patients treated with surgery with or without adjuvant chemotherapy, was studied. Intense TLI referred to a strong heavy lymphocytic infiltrate (intralobular and/or perilobular) of a density equivalent to that seen in a lymph node with metastasis.

The median follow-up was in both groups long enough (4.8 and 6 years, respectively) to draw reliable conclusions. TLI was intense in 11% of the patients in the discovery set compared with 6% in the validation set (P<0.001). TLI was prognostic for OS, DFS and SDFS in both the discovery set (OS: HR, 0.56; P=0.002; DFS: HR, 0.59; P=0.002; SDFS: HR, 0.56; P=0.003) and in the validation set (OS: HR, 0.45; P=0.01; DFS: HR, 0.44; P=0.005; SDFS: HR, 0.42; P=0.008). There was no heterogeneity across trials. Interestingly, no significant predictive effect for the use of adjuvant chemotherapy was observed for TLI (P≥0.78 for all end points).

Besides TLI, in the multivariate Cox model, also gender, WHO performance status, tumor stage and histology were significant prognostic factors for OS and PFS in the discovery and the validation set.

Although the proportion of patients with an intense TLI is small, it is surprising and unusual to observe such a strong influence on strong endpoints such as the OS. Moreover, TLI intense patients form a very heterogeneous population and the current study did not look at the specific lymphocytic subsets that may be related to the prognosis. It is conceivable that focusing on a specific cell subset within TLI could amplify its prognostic value.

Although a multivariate analysis was done, we do not have a prognostic model that incorporates all co-variates in a quantitative prognostic model. Clinicians do need this information, displayed as e.g., nomograms, in order to make decisions or to counsel patients. Although at the moment no therapeutic consequences should be considered in relation to the intensity of TLI, these models may give us information how much of the variability in survival is due to TLI vs. other prognostic parameters.

The findings of this study indicate that a strong tumor immune response has significant prognostic potential. Although Brambilla et al. could not show any predictive impact of TLI’s for chemotherapy, we should not dismiss the predictive potential of tumor immune infiltration too soon. Immune therapy has been searching for predictive parameters for several years, mainly focusing on expression of a specific therapy target like PD-L1. Testing TLI intensity in an immune therapy setting might still showcase it as instrument to select patients who gain the most therapy benefit. For example, it has already been suggested that parameters like CD8+ infiltration determine efficacy of immune therapy and radiotherapy combinations (19). Findings like these stress the importance of the immune environment in predictive and prognostic settings and thus, open up options for TLI to find additional clinical meaning. However, the broad nature of TLI obscures the specific immune cell subsets that play a role in an antitumor response, both positively like effector T cells and negatively like regulatory T cells. It might be beneficial to focus on a certain immune cell subset rather than pooling them into a general parameter like TLI if you want to find a therapy response predictor.

When testing TLI as a predictive parameter for (immune) therapy, another interesting question that must be asked is the impact of therapy on TLI itself. Immune therapy is currently not a first line treatment for NSCLC. Often, those patients have been exposed to radiation therapy of chemotherapy, which both have an impact on the tumor immune environment. Does this change prognostic and/or predictive impact of preoperatively determined TLI? The influence of different therapies on TLI itself is a big question mark that needs to be addressed if TLI is to be used in a clinical setting.

For the immediate future, it is key to dig into the details of the TLI and to characterize them in relation to genetic and microenvironment characteristics. In large databases such as used in the study of Brambilla et al. it may be possible to explore many fundamental questions regarding the immune biology of tumors. This will aid dramatically the improvement of immune therapy for lung cancer, which already now has led to long-lasting responses in patients with metastatic disease.

Acknowledgements

None.

Footnote

Provenance: This is an invited Commentary commissioned by the Section Editor Long Jiang (Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou, China).

Conflicts of Interest: The authors have no conflicts of interest to declare.

Comment on: Brambilla E, Le Teuff G, Marguet S, et al. Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34:1223-30.

References

1. Kataki A, Scheid P, Piet M, et al. Tumor infiltrating lymphocytes and macrophages have a potential dual role in lung cancer by supporting both host-defense and tumor progression. J Lab Clin Med 2002;140:320-8. [Crossref] [PubMed]
2. Ruffini E, Asioli S, Filosso PL, et al. Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thorac Surg 2009;87:365-71; discussion 371-2. [Crossref] [PubMed]
3. Johnson SK, Kerr KM, Chapman AD, et al. Immune cell infiltrates and prognosis in primary carcinoma of the lung. Lung Cancer 2000;27:27-35. [Crossref] [PubMed]
4. Gooden MJ, de Bock GH, Leffers N, et al. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 2011;105:93-103. [Crossref] [PubMed]
5. Dieu-Nosjean MC, Antoine M, Danel C, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 2008;26:4410-7. [Crossref] [PubMed]
6. Horne ZD, Jack R, Gray ZT, et al. Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in stage 1A non-small-cell lung cancer. J Surg Res 2011;171:1-5. [Crossref] [PubMed]
7. Schalper KA, Brown J, Carvajal-Hausdorf D, et al. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst 2015;107. [Crossref] [PubMed]
8. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 2013;31:860-7. [Crossref] [PubMed]
9. Adams S, Gray RJ, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 2014;32:2959-66. [Crossref] [PubMed]
10. Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol 2014;25:1544-50. [Crossref] [PubMed]
11. Wakabayashi O, Yamazaki K, Oizumi S, et al. CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci 2003;94:1003-9. [Crossref] [PubMed]
12. Hiraoka K, Miyamoto M, Cho Y, et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 2006;94:275-80. [Crossref] [PubMed]
13. Shimizu K, Nakata M, Hirami Y, et al. Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer. J Thorac Oncol 2010;5:585-90. [Crossref] [PubMed]
14. Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 2006;107:2866-72. [Crossref] [PubMed]
15. Kilic A, Landreneau RJ, Luketich JD, et al. Density of tumor-infiltrating lymphocytes correlates with disease recurrence and survival in patients with large non-small-cell lung cancer tumors. J Surg Res 2011;167:207-10. [Crossref] [PubMed]
16. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313:1960-4. [Crossref] [PubMed]
17. Nedergaard BS, Ladekarl M, Nyengaard JR, et al. A comparative study of the cellular immune response in patients with stage IB cervical squamous cell carcinoma. Low numbers of several immune cell subtypes are strongly associated with relapse of disease within 5 years. Gynecol Oncol 2008;108:106-11. [Crossref] [PubMed]
18. Brambilla E, Le Teuff G, Marguet S, et al. Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34:1223-30. [Crossref] [PubMed]
19. Dovedi SJ, Lipowska-Bhalla G, Beers SA, et al. Antitumor Efficacy of Radiation plus Immunotherapy Depends upon Dendritic Cell Activation of Effector CD8+ T Cells. Cancer Immunol Res 2016;4:621-30. [Crossref] [PubMed]