Evaluation of immunebiomarkers in lung cancer

• Autores: Pedro Filipe Simoes da Rocha
• Directores de la Tesis: Edurne Arriola Aperribay (dir. tes.), Montserrat Jaumot Pijoan (tut. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2022
• Idioma: inglés
• Tribunal Calificador de la Tesis: Jordi Giralt López de Sagredo (presid.), Irene Sansano (secret.), Margarita Majem (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
• Materias:
  • Ciencias médicas
    • Medicina interna
      • Enfermedades pulmonares
• Enlaces
  • Tesis en acceso abierto en:  TESEO  Dipòsit Digital de la UB 
• Resumen

  • Treatment landscape in early-stage NSCLC is rapidly changing after approval of anti-PD-1/PD-L1 in the neoadjuvant and adjuvant settings, respectively. However, biomarkers for patient selection, to predict response and to inform immunotherapeutic resistance are not available. Here we interrogate the expression patterns of CD73 in malignant cells and examined host anti-tumor immune response in order to describe and elucidate potential tumor mechanisms that promote immune evasion. We also assess immune biomarkers in early stage NSCLC surgical specimens. Finally, we evaluate immune features that promote response after chemotherapy or chemoimmunotherapy treatment, with the aim to uncover immune predictive and prognostic biomarkers in early-stage lung cancer. Our results pointed to the potential role of CD73, and other members of the adenosine signaling pathway, as potential mechanisms of tumor immune evasion and resistance to ICI, thus providing additional rationale for propagating anti-CD73 antibodies in new combinatorial immunotherapeutic regimens. We found that CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lung adenocarcinoma (LUAD). We observed that differential CD73 localization was associated with distinct clinicopathological and molecular features in LUAD. CD73 expression was positively associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Additionally, and using targeted gene sequencing analysis and immunohistochemistry, we characterized immune programs across patients that underwent upfront surgery, neoadjuvant chemotherapy, or neoadjuvant chemoimmunotherapy. We identified immune gene programs that are unique to PD-L1 positive and PD-L1 negative NSCLCs as well as those that are shared between both groups. Using IHC, we observed that PD-L1 positive (≥1%) LUADs exhibited an augmented infiltration of T cells (CD3+, CD4+, CD8+ cells) along with increase of FOXP3+ cells, resident memory cells (CD103+) and macrophages (CD68+). Spatial distribution of CD8+ T cells unveiled distinctive TIME phenotypes whose frequencies differed based on TNM stage, PD-L1 expression, and mutational burden. Inflamed and PD-L1+/TILs+ NSCLCs displayed significantly amplified lev- els of immune signatures, with the excluded group representing an intermediate immune state. Subgroup analysis based on the expression of tumor PD-L1, and resident memory immune cells (CD103+ cells) showed an enrichment of immune cell infiltrates (CD3+, CD4+, CD8+, CD68+ cells) in tumors harboring higher levels of CD103+ immune cells along with an increase of CD80+ cells, essential for T cell activation. Longitudinal analysis of patients following neoadjuvant chemoimmunotherapy showed strong upregulation of immune cells signatures within the TIME. In this cohort, pathologic response to chemoimmunotherapy was positively associated with higher expression of genes involved in immune activation, chemotaxis, as well as T and natural killer cells. Comparative analysis between the three cohorts, underscored immune programs and signatures that overall were progressively modulated along the spectrum of treatment-naïve, neoadjuvant chemotherapy-treated, up to those treated with chemoimmunotherapy, pointing to an association between perturbation of an expanded repertoire of immune gene sets with neoadjuvant chemoimmunotherapy. In conclusion, our findings suggest that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early-stage lung adenocarcinoma. Additionally, our results highlight immune gene programs and IHC markers that may underlie host tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC.