Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer

AbstractSmall-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.

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Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

10.21203/rs.3.rs-148314/v1 ◽

2021 ◽

Author(s):

Ming Chen ◽

Runzhe Chen ◽

Ying Jin ◽

Jun Li ◽

Jiexin Zhang ◽

...

Keyword(s):

Lung Cancer ◽

T Cell ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cell Receptor ◽

Small Cell ◽

Intratumor Heterogeneity ◽

High Recurrence Rate ◽

Small Cell Lung ◽

Tcr Repertoire

Abstract Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry (IHC), we revealed a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC (LS-SCLC) tumors. Compared to localized non-small cell lung cancers (NSCLCs), LS-SCLCs had similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression were associated with longer overall survival (OS), while higher CNA burden were associated with shorter OS in patients with LS-SCLC.

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The evolution of T-cell receptor repertoire in different stages of non-small cell lung cancer

10.21203/rs.3.rs-26421/v1 ◽

2020 ◽

Author(s):

Ziqi Jia ◽

Yadong Wang ◽

Xiaoying Yang ◽

Pancheng Wu ◽

Yanyu Wang ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Tumor Development ◽

Small Cell ◽

Small Cell Lung ◽

Tcr Repertoire

Abstract Background The intricate relationship between the tumor and host was not well understood, and antigen-specific T cell is fundamental in understanding the interaction. TCR repertoire analysis which described TCR clonotypes and TCR numbers has shown that TCRs with high frequency was tumor-specific T cells, while others might be ‘bystander’ T cells within tumors. However, how these “expanded” tumor-specific T cells was selected during the tumor development was not clear. Methods We retrospectively analyzed TCR sequencing and mutation sequencing results from 144 non-small cell lung cancer (NSCLC) patients. Results A rich TCR repertoire comprising thousands of different TCR sequences was identified in all stages of NSCLC, with most TCR clonotypes presented at low frequency. Interestingly, Stage IV NSCLC tumors contain more expanded TCRs as compared to earlier stages, however, lymph node metastasis or tumor size had little impact on expanded TCRs. Moreover, accumulation of mutations did not significantly change the number of TCR clonotypes, however, EGFR mutant patients had significantly lower while KRAS mutant patients had significantly higher number of TCR clonotypes especially in terms of those “expanded” TCRs. Conclusions In summary, T cells in the tumor microenvironment were gradually activated with tumor development. Critical events such as distal metastases and generation of EGFR or KRAS mutations might be the major factors affecting the changing of tumor-specific T cells in the tumor microenvironment.

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Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

10.1101/2020.06.30.180844 ◽

2020 ◽

Author(s):

Ming Chen ◽

Runzhe Chen ◽

Ying Jin ◽

Jun Li ◽

Jiexin Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cell Receptor ◽

Small Cell ◽

Intratumor Heterogeneity ◽

High Recurrence Rate ◽

Small Cell Lung ◽

Lung Cancers ◽

Tcr Repertoire

AbstractSmall-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

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Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery

Immunity ◽

10.1016/j.immuni.2021.02.014 ◽

2021 ◽

Vol 54 (3) ◽

pp. 586-602.e8

Author(s):

Shin-Heng Chiou ◽

Diane Tseng ◽

Alexandre Reuben ◽

Vamsee Mallajosyula ◽

Irene S. Molina ◽

...

Keyword(s):

Lung Cancer ◽

T Cell ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Global Analysis ◽

Small Cell ◽

Small Cell Lung ◽

Antigen Discovery

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Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

npj Precision Oncology ◽

10.1038/s41698-021-00203-1 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Marianne Oulhen ◽

Patrycja Pawlikowska ◽

Tala Tayoun ◽

Marianna Garonzi ◽

Genny Buson ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Copy Number ◽

Epithelial To Mesenchymal Transition ◽

Kinase Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition ◽

Anaplastic Lymphoma

AbstractGatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed highly altered CNA profiles and high levels of chromosomal instability (CIN). Half of CTCs displayed a ploidy >2n and 32% experienced whole-genome doubling. Hierarchical clustering showed significant intra-patient and wide inter-patient CTC diversity. Classification of 121 oncogenic drivers revealed the predominant activation of cell cycle and DNA repair pathways and of RTK/RAS and PI3K to a lower frequency. CTCs showed wide CNA heterogeneity and elevated CIN at resistance to ALK-TKIs. The emergence of epithelial ALK-negative CTCs may drive resistance through activation of bypass signaling pathways, while ALK-rearranged CTCs showed epithelial-to-mesenchymal transition characteristics potentially contributing to ALK-TKI resistance. Comprehensive analysis of CTCs could be of great help to clinicians for precision medicine and resistance to ALK-targeted therapies.

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