SCLC Subtypes and Biomarkers of the Transformative Immunotherapy Responses.

Despite a highly mutated genome, few SCLCs respond to immune checkpoint blockade (ICB). Only 12% to 18% of patients with SCLC treated with first-line chemotherapy-ICB combination remain progression free at 1 year.1Horn L. Mansfield A.S. Szczęsna A. et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.N Engl J Med. 2018; 379: 2220-2229Crossref PubMed Scopus (1819) Google Scholar,2Paz-Ares L. Dvorkin M. Chen Y. et al.Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.Lancet. 2019; 394: 1929-1939Abstract Full Text Full Text PDF PubMed Scopus (1013) Google Scholar Similarly, in the second- or third-line setting, a comparable proportion of patients exhibit tumor responses to single-agent ICB.3Goldman J.W. Dowlati A. Antonia S.J. et al.Safety and antitumor activity of durvalumab monotherapy in patients with pretreated extensive disease small-cell lung cancer (ED-SCLC).J Clin Oncol. 2018; 36 (8518–8518)PubMed Google Scholar,4Ready N. Farago A.F. de Braud F. et al.Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032.J Thorac Oncol. 2019; 14: 237-244Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar Nevertheless, ICB-mediated responses can be durable and transformative; 34% of patients who received first-line chemotherapy-ICB combination were alive at 18 months compared with 21% of patients who received chemotherapy alone.5Liu S.V. Reck M. Mansfield A.S. et al.Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133).J Clin Oncol. 2021; 39: 619-630Crossref PubMed Scopus (226) Google Scholar Identification of reliable biomarkers is therefore crucial to identify the subsets of patients with SCLC who are most likely to derive durable benefit from ICB. Several studies have evaluated tumor intrinsic and tumor extrinsic mechanisms that could serve as predictive biomarkers (Fig. 1). Clinical benefit from the addition of ICB to first-line chemotherapy was observed irrespective of programmed death-ligand 1 expression and tumor mutational burden.5Liu S.V. Reck M. Mansfield A.S. et al.Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133).J Clin Oncol. 2021; 39: 619-630Crossref PubMed Scopus (226) Google Scholar However, among previously treated patients with SCLC, those with a high tumor mutational burden derived greater benefit from nivolumab alone or in combination with ipilimumab.6Ricciuti B. Kravets S. Dahlberg S.E. et al.Use of targeted next generation sequencing to characterize tumor mutational burden and efficacy of immune checkpoint inhibition in small cell lung cancer.J Immunother Cancer. 2019; 7: 87Crossref PubMed Scopus (54) Google Scholar,7Hellmann M.D. Callahan M.K. Awad M.M. et al.Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer.Cancer Cell. 2018; 33: 853-861.e4Abstract Full Text Full Text PDF PubMed Scopus (597) Google Scholar SCLC exhibits substantial intertumor heterogeneity, classified based on the expression level of neuroendocrine genes to high-neuroendocrine (NE) and non-NE tumors,8Lissa D. Takahashi N. Desai P. et al.Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models.Nat Commun. 2022; 13: 2023Crossref PubMed Scopus (19) Google Scholar further defined by differential expression of the lineage-defining transcription factors ASCL1, NEUROD1, POU2F3, and YAP1 (SCLC-A, -N, -P, or -Y).9Rudin C.M. Poirier J.T. Byers L.A. et al.Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.Nat Rev Cancer. 2019; 19 (415–415)Google Scholar Patients with SCLC-Y tumors and SCLC-I, a transcriptional subtype characterized by reduced expression of the lineage-defining transcription factors, derived the most clinical benefit with the addition of ICB to first-line chemotherapy,10Mingchao Xie P.C. Broadhurst H. Lai Z. et al.Durvalumab (D) + platinum-etoposide (EP) in 1L extensive-stage small-cell lung cancer (ES-SCLC): exploratory analysis of SCLC molecular subtypes in CASPIAN.Cancer Res. 2022; 82 (Abstract nr CT024)Google Scholar,11Gay C.M. Stewart C.A. Park E.M. et al.Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities.Cancer Cell. 2021; 39 (346–360.e7)Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar likely due to increased tumor immune cell infiltration in these subtypes. MYC and Notch expression, which mediate SCLC plasticity between NE and non-NE states and predicts elevated antigen processing and presenting machinery (APM) and pretreatment cytotoxic tumor-infiltrating T cells, also identify tumors that are more likely to benefit from ICB.12Roper N. Velez M.J. Chiappori A. et al.Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer.Nat Commun. 2021; 12: 3880Crossref PubMed Scopus (51) Google Scholar,13Thomas A. Vilimas R. Trindade C. et al.Durvalumab in combination with olaparib in patients with relapsed SCLC: results from a phase II study.J Thorac Oncol. 2019; 14: 1447-1457Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar In this issue of the Journal of Thoracic Oncology, Rudin et al.14Rudin C.M. Balli D. Lai W.V. et al.Clinical benefit from immunotherapy in patients with SCLC is associated with tumor capacity for antigen presentation.J Thorac Oncol. 2023; 18: 1222-1232Abstract Full Text Full Text PDF Scopus (3) Google Scholar report post hoc analysis of CheckMate-032, a multicenter, open-label, phase I–II trial evaluating nivolumab or nivolumab plus ipilimumab for relapsed SCLC, including 401 patients. RNA sequencing was performed on 286 pretreatment tumors, classifying them into subtypes SCLC-A, -N, -P, or -Y, on the basis of the single highest expressing transcription factor.14Rudin C.M. Balli D. Lai W.V. et al.Clinical benefit from immunotherapy in patients with SCLC is associated with tumor capacity for antigen presentation.J Thorac Oncol. 2023; 18: 1222-1232Abstract Full Text Full Text PDF Scopus (3) Google Scholar These subtypes and other gene expression signatures were evaluated in relation to outcomes to predict patients who are most likely to benefit from immunotherapy. YAP1 expression was associated with an inflammation gene signature (R = 0.25, p = 0.00014), and SCLC-Y tumors had higher expression of APM (HLA-A, HLA-B, HLA-C, B2M, TAP1, and TAP2) genes (p < 0.000001). Furthermore, SCLC-Y was associated with macrophage and natural killer cell signatures compared with the other SCLC subtypes. Nevertheless, SCLC subtypes did not correlate with ICB outcomes. Rather, higher expression of APM genes (p = 0.000032) and abundance of CD8+ T-cell infiltration (≥1% by immunohistochemistry, hazard ratio = 0.51; 95% confidence interval: 0.27–0.95) were associated with improved overall survival. Consistently, APM was highly correlated with an inflammation gene signature (R = 0.75, p = 2.2e-16) and was the top enriched pathway in tumors from patients with durable benefit, with progression-free survival lasting at least 6 months. Collectively, these findings underscore the functional mechanism of ICBs; without antigen presentation or CD8+ T-cell infiltration, one would predict minimal therapeutic benefit. These findings align with previous observations across various cancer types, revealing the close relationship between ICB response and antigen processing and APM. APM facilitates T-cell recognition and immune-mediated clearance.15Jhunjhunwala S. Hammer C. Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion.Nat Rev Cancer. 2021; 21: 298-312Crossref PubMed Scopus (370) Google Scholar Suppression of APM may explain the limited efficacy of ICB in certain patients with SCLC, owing to reduced or eliminated B2M in some tumors and TAP in others. The authors propose an alternative model, suggesting a co-expression network governed by a shared epigenetic mechanism that regulates transcription. This should not be surprising given that the HLA gene complex is found in a short 3-Mbp region in chromosome 6, p-arm at 21.3. Nevertheless, an important caveat to the proposed theory is that bulk RNA sequencing data may lack the resolution to identify sporadically down-regulated genes in the MHC pathway, especially if the starting material includes normal tissue. Challenges to acquisition of high-quality tumor tissue for molecular characterization have severely limited our understanding of the molecular bases of SCLC response and resistance. In this context, it is notable that the report by Rudin et al. represents the largest data set to date to evaluate pretreatment transcriptional profiles of recurrent SCLC treated with ICB. Because not all study subjects explicitly agreed to public release of detailed genomic and transcriptomic profiles from their biospecimens, the data will not be publicly available. It is important to note that the findings from the current study are on the basis of ICB treatment of patients with relapsed SCLC, which is not the current practice and the post hoc exploratory nature of the analysis. Another limitation is that prestudy biospecimen collection relative to immunotherapy was variable, and some archived samples obtained at the time of diagnosis may not reflect the tumor state at the time of the study entry. Nevertheless, on the basis of these results, restoration of APM represents a rational approach that improves ICB clinical benefit for patients with SCLC. In preclinical studies, pharmacologic inhibition of the LSD1 demethylase activated Notch, suppressed NE features, restored MHC-I cell surface expression, and activated APM.16Nguyen E.M. Taniguchi H. Chan J.M. et al.Targeting lysine-specific demethylase 1 rescues major histocompatibility complex class I antigen presentation and overcomes programmed death-ligand 1 blockade resistance in SCLC.J Thorac Oncol. 2022; 17: 1014-1031Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar,17Hiatt J.B. Sandborg H. Garrison S.M. et al.Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T-cell killing.Clin Cancer Res. 2022; 28: 4551-4564Crossref PubMed Scopus (16) Google Scholar Similarly, pharmacologic inhibition of the EZH2 promoted epigenetic recovery of MHC-I, expanded non-NE cells, and restored APM.18Burr M.L. Sparbier C.E. Chan K.L. et al.An evolutionarily conserved function of Polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer.Cancer Cell. 2019; 36: 385-401.e8Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar,19Mahadevan N.R. Knelson E.H. Wolff J.O. et al.Intrinsic immunogenicity of small cell lung carcinoma revealed by its cellular plasticity.Cancer Discov. 2021; 11: 1952-1969Crossref PubMed Scopus (57) Google Scholar Taken together, preclinical and clinical data are pointing to strategies that enhance APM as an exciting new approach for rendering SCLC more responsive to ICB. Host factors—for example, germline genetics, composition of the gut microbiota—and the composition of the tumor microenvironment may also influence SCLC ICB response and should be explored in future studies. It is important to note that SCLC subtyping is an evolving area, and newer subtypes and the extent of plasticity and intratumoral heterogeneity is only beginning to be understood. Bispecific T cell engagers are emerging as an alternative strategy to render SCLC responsive to immune activation, bypassing APM and directly bridging the T cell and tumor cell. Whether and how these predictors of ICB responses determine responses to bispecific T cell engagers remains to be determined. The following individuals have made significant contributions to the conception, design, execution, and interpretation of the research study, including the drafting and revision of this manuscript. Their expertise and collaborative efforts have been instrumental in the completion of this work: Brett A. Schroeder: Writing - original draft; Writing - review & editing Anish Thomas: Writing - original draft; Writing - review & editing The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the manuscript reflect solely those of the authors. The authors take full responsibility for the content of this manuscript and ensure that all ethical guidelines and regulations were followed throughout the research process. Clinical Benefit From Immunotherapy in Patients With SCLC Is Associated With Tumor Capacity for Antigen PresentationJournal of Thoracic OncologyVol. 18Issue 9PreviewA small percentage of patients with SCLC experience durable responses to immune checkpoint blockade (ICB). Defining determinants of immune response may nominate strategies to broaden the efficacy of immunotherapy in patients with SCLC. Prior studies have been limited by small numbers or concomitant chemotherapy administration. Full-Text PDF