Immune Cell Infiltration Influences Long-Term Survivorship of Patients with SCLC
Authors: Yuanliang Yan, Wanli Liu, Min Liu, Zhicheng Gong, Zhijie Xu
Journal: Journal of Thoracic Oncology (2019)

We have read with interest the article by Muppa et al.1Muppa P. Parrilha Terra S.B. Sharma A. et al.Immune cell infiltration may be a key determinant of long-term survival in small cell lung cancer.J Thorac Oncol. 2019; 14: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar about the potential importance of immune cell infiltration for long-term survivorship (LTS) in patients with SCLC. Through comparing the differentially expressed genes between patients with LTS and patients with short-term survivorship, the authors found enriched numbers of tumor-infiltrating and associated lymphocytes in tumors in patients with LTS. We would like to point out some of the concerns regarding the immunological tumor microenvironment in the SCLC populations. Emerging studies have indicated that patient characteristics have an influence on the prevalence of immune-related genes in patients with lung cancer. Recently, Boothman et al. demonstrated that several clinical factors, such as the storage time of the paraffin specimen and prior chemoradiotherapy, result in significantly enhanced tumor expression of programmed death ligand 1.2Boothman A.M. Scott M. Ratcliffe M. et al.Impact of patient characteristics, prior therapy, and sample type on tumor cell PD-L1 expression in patients with advanced NCSLC screened for the ATLANTIC study [e-pub ahead of print]. J Thorac Oncol.https://doi.org/10.1016/j.jtho.2019.04.025Date accessed: July 11, 2019Google Scholar The samples from patients with SCLC that were screened in the study by Muppa et al.1Muppa P. Parrilha Terra S.B. Sharma A. et al.Immune cell infiltration may be a key determinant of long-term survival in small cell lung cancer.J Thorac Oncol. 2019; 14: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar were mainly taken from the archival formalin-fixed paraffin embedded surgical tissue specimens (sample age >3 months). The fresh biopsy specimens should be reanalyzed to provide a more accurate assessment of current immune cell profiling in individual SCLC tumors. Muppa et al.1Muppa P. Parrilha Terra S.B. Sharma A. et al.Immune cell infiltration may be a key determinant of long-term survival in small cell lung cancer.J Thorac Oncol. 2019; 14: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar also revealed higher counts of immunosuppressive lymphocytes (forkhead box p3–positive, CD68 molecule–positive, and CD14 molecule–positive) in the tumors of patients with LTS. And the expression levels of programmed cell death 1 (PD-1) and/or programmed death ligand 1 were obviously improved in all these immunosuppressive cells. However, the ratios of immunosuppressive cells to infiltrating T lymphocytes were much lower in patients with LTS, supporting the activated antitumor immunity. A recently published report from Kamada et al.3Kamada T. Togashi Y. Tay C. et al.PD-1(+) regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer.Proc Natl Acad Sci U S A. 2019; 116: 9999-10008Crossref PubMed Scopus (443) Google Scholar indicated that PD-1–positive/forkhead box p3–positive immunosuppressive lymphocytes amplified by PD-1 blockade could significantly promote the hyperprogressive disease in human solid cancers, leading to suppression of antitumor immune responses. Thus, the detailed functions of suppressive lymphocytes in the tumor microenvironment warrant further investigation. In addition, other researchers have evaluated the prognostic significance of nonimmunological biomarkers in patients with SCLC. For example, Calbo et al.4Calbo J. van Montfort E. Proost N. et al.A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer.Cancer Cell. 2011; 19: 244-256Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar examined tumor cell heterogeneity and found that SCLC-derived tumor cells are often characterized by neuroendocrine or mesenchymal marker profiles. The expression levels of these molecular biomarkers have been proved to be associated with disease development and prognosis.5Gazdar A.F. Bunn P.A. Minna J.D. Small-cell lung cancer: what we know, what we need to know and the path forward.Nat Rev Cancer. 2017; 17: 725-737Crossref PubMed Scopus (416) Google Scholar Considering the application in clinical practice, we assume that a more precision prediction of LTS might come from the composite immune-related and non–immune-related molecular signature. This work was supported by National Natural Science Foundation of China (grants 81703036, 81803035, and 81572946). Response to Letter to the EditorJournal of Thoracic OncologyVol. 14Issue 11PreviewWe appreciate the careful evaluations and the concerns raised by Yan et al.1 referencing our article.2 The first concern relates to the type of specimens used in our study and the possibility that the expression of immune-related markers, such as programmed death ligand 1 (PD-L1), may have been low because of the storage times of the paraffin-embedded samples and the likelihood that these blocks were from patients who did not have prior therapies. In support of this argument, Yan et al.1 cite a recent publication by Boothman et al. Full-Text PDF Open Archive