Analyzing the Thin Tail: Searching for Biomarkers of Exceptional Survival in SCLC
Authors: W. Victoria Lai, Charles M. Rudin
Journal: Journal of Thoracic Oncology (2019)

The prognosis of patients with SCLC remains remarkably dismal with a median overall survival of 15 to 20 months for limited-stage disease and 8 to 13 months for extensive-stage disease.1Osterlind K. Hansen H.H. Hansen M. Dombernowsky P. Andersen P.K. Long-term disease-free survival in small-cell carcinoma of the lung: a study of clinical determinants.J Clin Oncol. 1986; 4: 1307-1313Google Scholar For many years, the standard of care for SCLC therapy remained unchanged with platinum and etoposide as the first-line regimen followed by topotecan as subsequent-line treatment. We finally saw some new additions to the armamentarium in the past year: immune checkpoint blockade using nivolumab was granted accelerated approval by the US Food and Drug Administration in August 2018 for subsequent-line therapy of recurrent SCLC, and in September 2018, initial results from IMPower133, a multicenter randomized phase III study that investigated the outcomes of adding atezolizumab to initial chemotherapy followed by maintenance atezolizumab, changed initial first-line therapy for SCLC for the first time in several decades.2Ready N. Farago A.F. de Braud F. et al.Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032.J Thorac Oncol. 2019; 14: 237-244Google Scholar, 3Horn L. Mansfield A.S. Szczesna A. et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.N Engl J Med. 2018; 379: 2220-2229Google Scholar Despite these recent advances, however, long-term survival in patients with SCLC remains extremely rare. Prior studies have shown that patients with SCLC have survival rates less than 5% and 2% at their 5-year and 10-year follow-ups, respectively.4Lassen U. Osterlind K. Hansen M. Dombernowsky P. Bergman B. Hansen H.H. Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years—an analysis of 1,714 consecutive patients.J Clin Oncol. 1995; 13: 1215-1220Google Scholar Little is known about the determinants of long-term survival in patients with SCLC. Defining biomarkers of long-term survival in patients with SCLC could provide new insights into more successful therapeutic strategies for this disease. In this issue of the Journal of Thoracic Oncology, Muppa et al.5Muppa P. Terra S.B.S.P. 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: 1286-1295Google Scholar report findings from their study that sought to explore potential determinants of long-term survival in patients with SCLC. This was a case-control study that compared surgically resected SCLC tumors obtained at a single institution from 1985–2007. Patients with SCLC who survived 4 years or longer after their initial surgery were considered long-term survivors (LTS, n = 20), and patients who survived fewer than 2 years were considered to have expected survival and served as a comparison group (EXS, n = 17). Gene expression analyses were performed using microarrays, followed by pathway analyses. Immunohistochemistry (IHC) of the tumor microenvironment was used to corroborate findings from the gene expression analyses. In this study, transcriptional analysis revealed an overexpression of genes related to the immune response within the tumor microenvironment, regardless of clinical outcome. Forty-seven percent of the overexpressed probe sets corresponded to immunoglobulin or major histocompatibility complex (human leukocyte antigen) genes. Many of the remaining highly ranked differences were found in genes that play a role in tumor immunity, including genes such as beta-2-microglobulin (B2M), CD3e molecule (CD3E), or C-X-C motif chemokine ligand 9 (CXCL9). Protein expression of B2M and CXCL9 in the tumor tissues was evaluated by IHC, and B2M was found to be significantly increased in LTS compared with EXS (p = 0.005). Whereas CXCL9 had a higher median expression in LTS than EXS, the increased level of expression was not statistically significant. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed an enrichment of immune-related pathways, such as antigen presentation, in LTS when compared with EXS. These findings were corroborated by IHC staining of CD3+ lymphocytes in the tumor microenvironment, which showed a significantly higher number of tumor-infiltrating lymphocytes (TILs) in the tumor stroma in LTS. Specifically, both CD4+ and CD8+ T lymphocytes were significantly higher in LTS than in EXS. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) staining were enriched in TILs of the LTS. Consistent with previously reported findings, PD-1/PD-L1 staining via IHC in the tumor cells was either negative or very weak. The authors also investigated a wider panel of immunological markers in each tumor. Whereas more TILs were found on average in LTS when compared to EXS, tumor infiltration was still variable among individual patients in the same cohort. In fact, it is notable that at least three LTS patients had tumors with reduced MHC-I expression, suggesting that the determinants of exceptional survival may involve mechanisms other than classic antitumor cytotoxic T cell responses. The authors also note higher concentrations of CD138+ cells in tumors from EXS than those from LTS.6Fooksman D.R. Mazumder A. McCarron M. CD138 regulates myeloma cell survival, proliferation.BM engraftment and tumor organization. 2015; 126 (2974-2974)Google Scholar Whereas CD138 is known to regulate and promote myeloma cell survival and its positivity in lung cancer has been established, this study is the first to suggest an association of CD138+ with shorter overall survival in SCLC.6Fooksman D.R. Mazumder A. McCarron M. CD138 regulates myeloma cell survival, proliferation.BM engraftment and tumor organization. 2015; 126 (2974-2974)Google Scholar, 7Toyoshima E. Ohsaki Y. Nishigaki Y. Fujimoto Y. Kohgo Y. Kikuchi K. et al.Expression of syndecan-1 is common in human lung cancers independent of expression of epidermal growth factor receptor.Lung Cancer. 2001; 31: 193-202Google Scholar An intriguing finding from this study was the trend towards higher absolute numbers of FOXP3+ lymphocytes in LTS. In general, FOXP3 identifies suppressive T cells (regulatory T cells or Tregs), which play the fundamental role of maintaining self-tolerance and immune homeostasis.8Sakaguchi S. Miyara M. Costantino C.M. Hafler D.A. FOXP3+ regulatory T cells in the human immune system.Nat Rev Immunol. 2010; 10: 490-500Google Scholar Notably, although the absolute number of Tregs was higher in the LTS group, their median normalized fraction of total CD3+ cells was not elevated. Select prior studies of solid tumor immune infiltrates have found an association between adverse outcome and the increased expression of FOXP3.9Curiel T.J. Coukos G. Zou L. et al.Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.Nat Med. 2004; 10: 942-949Google Scholar In vivo depletion of Tregs have led to tumor regression, suggesting logically that the presence of Tregs suppresses an effective immune response to tumor.10Zou W. Regulatory T cells, tumour immunity and immunotherapy.Nat Rev Immunol. 2006; 6: 295-307Google Scholar Although this reasoning may explain the findings reported here, it is in contrast to those reported in an earlier study that retrospectively analyzed 104 SCLC cases (66 were limited-stage and 38 were metastatic) and found that FOXP3+ TILs were present in 59% and 72% of samples, respectively.11Bonanno L. Pavan A. Dieci M.V. et al.The role of immune microenvironment in small-cell lung cancer: Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes.Eur J Cancer. 2018; 101: 191-200Google Scholar In this preceding study, the presence of FOXP3+ TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.37 (95% confidence interval: 0.17–0.81, p = 0.013) in multivariate analysis.11Bonanno L. Pavan A. Dieci M.V. et al.The role of immune microenvironment in small-cell lung cancer: Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes.Eur J Cancer. 2018; 101: 191-200Google Scholar Additionally, in an independent retrospective analysis of 32 brain metastases from SCLCs, CD8+ TILs were present in most samples (78%) and FOXP3+ TILs were present in 47% of cases, but no prognostic impact of either CD8+ or FOXP3+ TILs was observed.12Berghoff A.S. Ricken G. Wilhelm D. et al.Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC).J Neurooncol. 2016; 130: 19-29Google Scholar Taken together, these studies suggest that the roles of various TIL subsets are complex and dependent on both tumor type and context. This is in keeping with prior demonstration of the phenotypic and functional diversity of FOXP3+ TILs.8Sakaguchi S. Miyara M. Costantino C.M. Hafler D.A. FOXP3+ regulatory T cells in the human immune system.Nat Rev Immunol. 2010; 10: 490-500Google Scholar Without a complete understanding of the underlying biological mechanisms through which both Tregs and other TILs exert their function in this tumor type and context, characterization of tumor cell infiltration will not be enough to help us understand what determines prolonged survival in patients with SCLC. Further investigations in larger populations of patients with SCLC are needed to elucidate the complex role that Tregs and other TILs play in tumorigenesis and how they affect response to immunotherapy. One key limitation of this study is that the patients examined all underwent surgical resection, mostly with curative intent. Many of these patients presented with very early limited-stage disease, which represents a small subset of patients who are diagnosed with SCLC. This limits our ability to extrapolate these findings to the more typical SCLC patients whose disease is not amenable to surgery. Nevertheless, this report provides needed early insights into potential determinants of long-term survival in patients with SCLC and suggests a role for increased immune infiltration in the tumor microenvironment as a determinant of improved patient outcomes. The authors' findings are thought-provoking and may have implications for the use of immunotherapy as systemic treatment. This study further underscores the importance for investigations that explore predictive biomarkers of long-term patient outcomes. Identification and deeper understanding of these biomarkers may enable us to tailor treatment to individual patients and to develop new therapeutics more broadly effective for patients with this aggressive disease. Immune Cell Infiltration May Be a Key Determinant of Long-Term Survival in Small Cell Lung CancerJournal of Thoracic OncologyVol. 14Issue 7PreviewAlthough most patients with SCLC die within a few months of diagnosis, a subgroup of patients survive for many years. Factors determining long-term survivorship remain largely unknown. We present the first comprehensive comparative genomic and tumor microenvironment analyses of SCLC between patients with long-term survivorship and patients with the expected survivorship. Full-Text PDF Open Access