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155 MHC class I antigen presentation is associated with an inflamed SCLC tumor microenvironment characterized by a higher density of cytotoxic T-cells in closer proximity to tumor cells
  1. Miljenka Vuko,
  2. Mingchao Xie,
  3. Monica Azqueta Gavaldon,
  4. Felix Segerer,
  5. Andreas Spitzmüller,
  6. Harald Hessel,
  7. Marco Testori,
  8. Johannes Zimmermann,
  9. Michael Surace,
  10. Mari Heininen-Brown,
  11. Jaime Rodriguez Canales,
  12. Shashank Saran,
  13. Helen Angell,
  14. Guenter Schmidt,
  15. Hadassah Sade,
  16. J Carl Barrett,
  17. Markus Schick and
  18. Giulia Fabbri
  1. AstrZeneca, Munich, Germany


Background Small cell lung cancer (SCLC) is generally known to exclude immune cells and durable responses to immunotherapies are rare. Only very few biomarkers to inform immuno-oncology (IO) treatments are established in clinical practice thus far. Recently, four major SCLC subtypes (SCLC-A, SCLC-N, SCLC-P and SCLC-I) were described. Whereas the first three are characterized by activation of specific transcription factors, the SCLC-I (inflamed) subtype is characterized by an inflamed gene signature, high expression of MHC class I (MHC-I) antigen presentation and shows the greatest benefit from addition of immunotherapy to chemotherapy treatment [1,2]. Importantly, MHC-I is epigenetically silenced in the vast majority of SCLC and the presence of MHC-I could serve as a biomarker for the identification of SCLC-I cases. [2]. Here, we aimed to assess the biology of MHC-I high SCLC cases to investigate its role as a biomarker to inform cancer immunotherapies.

Methods We combined the power of artificial intelligence (AI)-driven computational pathology with multiplex immunofluorescence (mIF) to gain critical insight into the tumor microenvironment (TME) of SCLC. 125 SCLC formalin-fixed, paraffin-embedded tissue samples were stained with a mIF panel consisting of six markers: PanCK, CD8, CD68, PD-1, PD-L1, and Ki67. We assessed the phenotype and spatial location of each cell in the pathologist-annotated tumor center and within the AI-segmented stroma and tumor epithelium. Pathologists classified immunohistochemically stained MHC-I slides from the same tissue blocks as MHC-I high, medium, or low according to their H-scores (low: ≤30; medium: 31–139; high: ≥140). TME characteristics between those groups were compared.

Results In all measured regions, we found higher densities of CD8+ and particularly PD-1/CD8 double positive T-cells in the MHC-I high group. Moreover, we observed the highest proportion of PD-1 positivity among cytotoxic T-cells in the tumor epithelium of MHC-I high samples, which also showed a high density of PD-L1+ tumor cells. Average distance of PD-1+ T-cells to their nearest tumor cell was lowest in the MHC-I high group. In the same group, an average of 19.3% of tumor cells in the epithelium had at least one PD-1+ T-cell within a 50 µm radius, while in the MHC-I low group this average was only 8.9%.

Conclusions We utilized cutting-edge computational pathology to establish MHC-I as orchestrator of the composition and spatial arrangement of an inflamed SCLC TME. Beyond that, our findings corroborate the role of MHC-I as a potential biomarker for inflamed SCLC cases, which benefit most from cancer immunotherapies.


  1. Gay CM, Stewart CA, Park EM, Diao L, Groves SM, Heeke S, Nabet BY, Fujimoto J, Solis LM, Lu W, Xi Y, Cardnell RJ, Wang Q, Fabbri G, Cargill KR, Vokes NI, Ramkumar K, Zhang B, Della Corte CM, Robson P, Swisher SG, Roth JA, Glisson BS, Shames DS, Wistuba II, Wang J, Quaranta V, Minna J, Heymach JV, Byers LA. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021 Mar 8;39(3):346–360.e7. doi: 10.1016/j.ccell.2020.12.014. Epub 2021 Jan 21. PMID: 33482121; PMCID: PMC8143037.

  2. Mahadevan NR, Knelson EH, Wolff JO, Vajdi A, Saigí M, Campisi M, Hong D, Thai TC, Piel B, Han S, Reinhold BB, Duke-Cohan JS, Poitras MJ, Taus LJ, Lizotte PH, Portell A, Quadros V, Santucci AD, Murayama T, Cañadas I, Kitajima S, Akitsu A, Fridrikh M, Watanabe H, Reardon B, Gokhale PC, Paweletz CP, Awad MM, Van Allen EM, Lako A, Wang XT, Chen B, Hong F, Sholl LM, Tolstorukov MY, Pfaff K, Jänne PA, Gjini E, Edwards R, Rodig S, Reinherz EL, Oser MG, Barbie DA. Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity. Cancer Discov. 2021 Aug;11(8):1952–1969. doi: 10.1158/2159-8290.CD-20-0913. Epub 2021 Mar 11. PMID: 33707236; PMCID: PMC8338750.

Ethics Approval All samples from which data in this report were generated, were obtained from an internal repository. All protocols, amendments, and participant informed consent documents were approved by the appropriate institutional review boards.

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