Final Report Summary - NKG2D (CO-OPTION OF THE NKG2D LYMPHOCYTE RECEPTOR AS AN ONCOPROTEIN PROMOTING CANCER STEM CELL TRANSDIFFERENTIATION AND CANCER AUTONOMY)
Comprehensive characterization of the immune landscape in non-small cell lung cancer
The success of immune checkpoint inhibitors (ICI) for non- small cell lung cancer (NSCLC) has galvanized the field. Unfortunately, just ~20% of patients benefit from novel therapies and underlying mechanisms for treatment failure are mostly unknown. ICI therapy likely fails for one of two reasons: (1) an antigen-driven immune response is not present or (2) an antigen-driven immune response is present, but immune suppressive factors reside within the tumor microenvironment (TME) that derail an otherwise effective immune response.
Lung cancer, the leading cause of cancer deaths, is a heterogeneous disease classified by histologic subtypes, with adenocarcinoma (ADCA) and squamous cell carcinoma (SCCA) representing the majority of NSCLC. Just as the anatomical location and mutational signature of the NSCLC subtypes differ, one would expect that the immune cell composition and function would also differ. A strong foundational knowledge of the immune cell composition in NSCLC, will likely prove prerequisite to realizing the full potential of such reagents.
To evaluate the complexity of the immune landscape in NSCLC we examined tumor and non-adjacent lung tissue in a cohort of 73 patients. We used flow cytometry, fluorescent multiplex immunohistochemistry and gene expression analysis to comprehensively profile the immune cell content and function in attempts to identify the dominant immune suppressive factors. Further, we performed T cell receptor sequencing to delineate the frequency with which antigen-driven immune responses exist. The additional analysis of somatic mutations, gene fusions and signaling pathways of the same cohort allowed the comprehensive characterization of NSCLC.
We could show that many immune cell types are significantly increased in tumor, when compared to non-adjacent lung. Cluster analysis identified patient groups with immune inactive and exhausted adaptive immunity and immune cell compositions are unique for NSCLC subtypes. In SCCA we observed a neutrophil predominant signature with additional increased infiltration of Treg when compared to ADCA. SCCA displays immune suppressive cell content, indicated by high expression of exhaustion markers on T-cells (PD-1, TIM3). Further, a more clonal TCRβ repertoire was observed in SCCA, indicating the presence of an antigen-driven immune response. Further, we identified that neutrophils constrain adaptive immune responses and neutrophils were the most abundant immune cell type in NSCLC specimens. A strong negative correlation between neutrophil and CD8+ cellular content was observed. Notably, this association did not exist in non-adjacent lung tissue, strongly suggesting that this is a tumor-specific phenomenon.
This multidimensional dataset provides evidence that the immune landscape present within different NSCLC subtypes displays unique phenotypes and identifying the immunosuppressive factors in different subsets will be important for successful immune-based therapy.
The success of immune checkpoint inhibitors (ICI) for non- small cell lung cancer (NSCLC) has galvanized the field. Unfortunately, just ~20% of patients benefit from novel therapies and underlying mechanisms for treatment failure are mostly unknown. ICI therapy likely fails for one of two reasons: (1) an antigen-driven immune response is not present or (2) an antigen-driven immune response is present, but immune suppressive factors reside within the tumor microenvironment (TME) that derail an otherwise effective immune response.
Lung cancer, the leading cause of cancer deaths, is a heterogeneous disease classified by histologic subtypes, with adenocarcinoma (ADCA) and squamous cell carcinoma (SCCA) representing the majority of NSCLC. Just as the anatomical location and mutational signature of the NSCLC subtypes differ, one would expect that the immune cell composition and function would also differ. A strong foundational knowledge of the immune cell composition in NSCLC, will likely prove prerequisite to realizing the full potential of such reagents.
To evaluate the complexity of the immune landscape in NSCLC we examined tumor and non-adjacent lung tissue in a cohort of 73 patients. We used flow cytometry, fluorescent multiplex immunohistochemistry and gene expression analysis to comprehensively profile the immune cell content and function in attempts to identify the dominant immune suppressive factors. Further, we performed T cell receptor sequencing to delineate the frequency with which antigen-driven immune responses exist. The additional analysis of somatic mutations, gene fusions and signaling pathways of the same cohort allowed the comprehensive characterization of NSCLC.
We could show that many immune cell types are significantly increased in tumor, when compared to non-adjacent lung. Cluster analysis identified patient groups with immune inactive and exhausted adaptive immunity and immune cell compositions are unique for NSCLC subtypes. In SCCA we observed a neutrophil predominant signature with additional increased infiltration of Treg when compared to ADCA. SCCA displays immune suppressive cell content, indicated by high expression of exhaustion markers on T-cells (PD-1, TIM3). Further, a more clonal TCRβ repertoire was observed in SCCA, indicating the presence of an antigen-driven immune response. Further, we identified that neutrophils constrain adaptive immune responses and neutrophils were the most abundant immune cell type in NSCLC specimens. A strong negative correlation between neutrophil and CD8+ cellular content was observed. Notably, this association did not exist in non-adjacent lung tissue, strongly suggesting that this is a tumor-specific phenomenon.
This multidimensional dataset provides evidence that the immune landscape present within different NSCLC subtypes displays unique phenotypes and identifying the immunosuppressive factors in different subsets will be important for successful immune-based therapy.