Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer

Pennycuick, Adam; Teixeira, Vítor Hugo; AbdulJabbar, Khalid; Raza, Shan E. Ahmed; Lund, Tom; Akarca, Ayse U.; Rosenthal, Rachel; Kalinke, Lukas; Chandrasekharan, Deepak; Pipinikas, Christodoulos P.; Lee-Six, Henry; Hynds, Robert E.; Gowers, Kate H.C.; Henry, Jake Y.; Millar, Fraser R.; Hagos, Yeman Brhane; Denais, Céline; Falzon, Mary; Moore, David A.; Antoniou, Sophia; Durrenberger, Pascal F.; Furness, Andrew J.S.; Carroll, Bernadette; Marceaux, Claire; Asselin-Labat, Marie-Liesse; Larson, William D.; Betts, Courtney B.; Coussens, Lisa M.; Thakrar, Ricky; George, Jeremy; Swanton, Charles; Thirlwell, Christina; Campbell, Peter J.; Marafioti, Teresa; Yuan, Yinyin; Quezada, Sergio A.; McGranahan, Nicholas; Janes, Sam M.

doi:10.1158/2159-8290.cd-19-1366

Cited by 65 publications

(75 citation statements)

References 50 publications

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“…Proliferative subtype PMLs that progressed or persisted were depleted of innate and adaptive immune cells and demonstrated decreased expression of interferon signaling and antigen presentation pathways. Additional studies have shown that high-grade or progressive/persistent PMLs are associated with an immunosuppressive microenvironment[10–12]. These findings support the hypothesis that the spontaneous adaptive immune response to premalignancy is a mechanism controlling PML-progression and that this might be therapeutically exploited for immunoprevention of cancer.…”

Section: Introductionsupporting

confidence: 61%

Elevated T cell repertoire diversity is associated with progression of lung squamous cell premalignant lesions

Maoz

Merenstein

Koga

et al. 2021

Preprint

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Objective: The immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological, and molecular features. Methods: Endobronchial biopsies (n=295) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via autofluorescence bronchoscopy and CT, were profiled by RNA-seq. We applied the TCR Repertoire Utilities for Solid Tissue/Tumor (TRUST) tool to the RNA-seq data to identify TCR CDR3 sequences across all samples. In the biopsies, we measured the correlation of TCR diversity with previously derived immune-associated PML transcriptional signatures and outcome. We also quantified the spatial and temporal distribution of shared and clonally expanded TCRs. Using the biopsies and brushes, the ratio of private (i.e., found in one patient only) and public (i.e., found in two or more patients) TCRs was quantified and the CDR3 sequences were compared to those found in curated databases with known antigen specificities. Results: We detected 39,303 unique TCR sequences across all samples. In PML biopsies, TCR diversity was negatively associated with a transcriptional signature of T-cell mediated immune activation (Spearman rho -0.34, p < 0.001) associated with PML outcome. Additionally, in lesions of the proliferative molecular subtype, TCR diversity was decreased in regressive versus progressive/persistent PMLs (p=0.045). Within each patient, TCRs were more likely to be shared between biopsies sampled at the same timepoint than biopsies sampled at the same anatomic location at different times. Clonally expanded TCRs, within a biopsied lesion, were more likely to be expanded at future time points than non-expanded clones. The majority of TCR sequences were found in a single sample, with only 3,396 (8.6%) found in more than one sample and 1,057 (2.7%) found in two or more patients (i.e. public), however, when compared to a public database of CDR3 sequences, 4,543 (11.6%) of TCRs were identified as public. TCRs with known antigen specificities were enriched among Public TCRs (p < 0.001). Conclusions: Decreased TCR diversity may reflect nascent immune responses that contribute to PML elimination. Further studies are needed to explore the potential for immunoprevention of PMLs.

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Section: Introductionsupporting

confidence: 61%

Elevated T cell repertoire diversity is associated with progression of lung squamous cell premalignant lesions

Maoz

Merenstein

Koga

et al. 2021

Preprint

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“…This could potentially be linked to individual variation at the HLA locus, 121 LOH in the HLA region or by inducing other mechanisms such as amplification of the immune checkpoint molecule programmed death ligand-1, 119,122,123 as was demonstrated by comparing preinvasive lesions of the lung that were immune-competent (and therefore regressed) with those that progressed. 124 Additionally, hypermethylation of the HLA region was also commonly observed 124 (Fig. 2a).…”

Section: Ex Vivo Drug Modulation Modifications Of Culturing Conditionmentioning

confidence: 80%

Promises and challenges of adoptive T-cell therapies for solid tumours

et al. 2021

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Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

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“…Recent studies have demonstrated an encouraging predictive potential of molecular and cellular features to distinguish regressive from progressive lesions. Specifically, the presence of M2 over M1 macrophages, 17 , 18 decreased T cell abundance, 17–19 higher number of somatic mutations and chromosomal instability, 20 impairments in the antigen presenting machinery 17 , 19 in premalignant bronchial lesions have been linked to an increased risk of progression. Moreover, TNFRSF9 (CD137), an important costimulatory molecule for T cell activation, and its high-affinity ligand TNFSF9 (CD137L, 41BBL) were the most distinguishably upregulated molecules in high-grade precancer and cancer.…”

Section: Leveraging Immunomodulatory Therapies For Early Detection and Chemopreventionmentioning

confidence: 99%

“… 2 Upregulation of CD137L in squamous lung premalignancy has been linked to a lower risk of progression. 19 Therefore, CD137 is a promising actionable candidate for promoting a prophylactic immune response by using readily available agonistic anti-CD137.…”

Section: Leveraging Immunomodulatory Therapies For Early Detection and Chemopreventionmentioning

confidence: 99%

Evasion before invasion: Pre-cancer immunosurveillance

2021

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Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer

Cited by 65 publications

References 50 publications

Elevated T cell repertoire diversity is associated with progression of lung squamous cell premalignant lesions

Elevated T cell repertoire diversity is associated with progression of lung squamous cell premalignant lesions

Promises and challenges of adoptive T-cell therapies for solid tumours

Evasion before invasion: Pre-cancer immunosurveillance

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