Immune Surveillance in Clinical Regression of Pre-Invasive Squamous Cell Lung Cancer

Pennycuick, Adam; Teixeira, Vítor Hugo; AbdulJabbar, Khalid; Raza, Shan E Ahmed; Lund, Tom; Akarca, Ayse U.; Rosenthal, Richard R.; Pipinikas, Christodoulos P.; Lee-Six, Henry; Chandrasekharan, Deepak; Hynds, Robert E.; Gowers, Kate H.C.; Henry, John A.; Denais, Céline; Falzon, M; Antoniou, Sophia; Durrenberger, Pascal F.; Furness, Andrew; Carroll, B.; Thakrar, Ricky M.; George, PJ; Marafioti, Teresa; Swanton, Charles; Thirlwell, Chrissie; Campbell, Peter J.; Yuan, Yinyin; Quezada, Sergio A.; McGranahan, Nicholas; Janes, Sam M.

doi:10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2531

“…Strikingly, clonal HLA LoH was only detected in ES patients in both early-stage and late-stage disease suggesting it is an early event in the evolution of ES tumours. Analysis of HLA LoH in preinvasive lung cancer lesions corroborates this observation where HLA LoH occurred in 34% of squamous carcinoma in situ in ES patients 62 , 8% of adenocarcinoma in situ/minimally invasive adenocarcinoma in ES patients and only 1% of these lesions in NS patients 51 . We propose that the TRM-rich microenvironment of ES lungs where NSCLC grows is a likely driver of this early immune evasion mechanism.…”

Section: Discussionsupporting

confidence: 70%

“…Oncogenic alterations and genomic instability are found in normal lung basal cells from heavy smokers 4,5 , yet not all ever-smokers will develop lung cancers 60 . Pre-invasive LUSC 61 possess mutations in oncogenic drivers including KRAS, EGFR and KEAP1 but a number of these lesions regress to a normal-like state 62 . The presence of CD8 + T cells infiltrating pre-malignant LUSC was proposed to support the elimination of malignant cells 62 .…”

Section: Discussionmentioning

confidence: 99%

“…Pre-invasive LUSC 61 possess mutations in oncogenic drivers including KRAS, EGFR and KEAP1 but a number of these lesions regress to a normal-like state 62 . The presence of CD8 + T cells infiltrating pre-malignant LUSC was proposed to support the elimination of malignant cells 62 . It is tempting to speculate greater TRM-immunosurveillance induced by tobacco smoking may protect from invasive cancers induced by this same insult.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Early immune pressure imposed by tissue resident memory T cells sculpts tumour evolution in non-small cell lung cancer

Weeden

¹

,

Gayevskiy

²

,

Trussart

³

et al. 2021

Preprint

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Tissue-resident memory T cells (TRM) provide immune defence against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and how the immune pressure exerted by TRM affects developing tumours in humans. We performed deep profiling of lung cancers arising in never-smokers (NS) and ever-smokers (ES), finding evidence of enhanced TRM immunosurveillance in ES lung. Only tumours arising in ES patients underwent clonal immune escape, even when evaluating cancers with similar tumour mutational burden to NS patients, suggesting that the timing of immune pressure exerted by TRM is a critical factor in the evolution of tumour immune evasion. Tumours grown in T cell quiescent NS lungs displayed little evidence of immune evasion and had fewer neoantigens with low diversity, paradoxically making them amenable to treatment with agonist of the costimulatory molecule, ICOS. These data demonstrate local environmental insults enhance TRM immunosurveillance of human tissue, shape the evolution of tumour immunogenicity and that this interplay informs effective immunotherapeutic modalities.

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“…Oncogenic alterations and genomic instability are found in normal lung basal cells from heavy smokers 4,5 , yet not all ever-smokers will develop lung cancers 60 . Pre-invasive LUSC 61 possess mutations in oncogenic drivers including KRAS, EGFR and KEAP1 but a number of these lesions regress to a normal-like state 62 . The presence of CD8 + T cells infiltrating pre-malignant LUSC was proposed to support the elimination of malignant cells 62 .…”

Section: Discussionmentioning

confidence: 99%

“…Pre-invasive LUSC 61 possess mutations in oncogenic drivers including KRAS, EGFR and KEAP1 but a number of these lesions regress to a normal-like state 62 . The presence of CD8 + T cells infiltrating pre-malignant LUSC was proposed to support the elimination of malignant cells 62 . It is tempting to speculate greater TRM-immunosurveillance induced by tobacco smoking may protect from invasive cancers induced by this same insult.…”

Section: Discussionmentioning

confidence: 99%

Early immune pressure imposed by tissue resident memory T cells sculpts tumour evolution in non-small cell lung cancer

Weeden

¹

,

Gayevskiy

²

,

Trussart

³

et al. 2021

Preprint

View full text Add to dashboard Cite

Tissue-resident memory T cells (TRM) provide immune defence against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and how the immune pressure exerted by TRM affects developing tumours in humans. We performed deep profiling of lung cancers arising in never-smokers (NS) and ever-smokers (ES), finding evidence of enhanced TRM immunosurveillance in ES lung. Only tumours arising in ES patients underwent clonal immune escape, even when evaluating cancers with similar tumour mutational burden to NS patients, suggesting that the timing of immune pressure exerted by TRM is a critical factor in the evolution of tumour immune evasion. Tumours grown in T cell quiescent NS lungs displayed little evidence of immune evasion and had fewer neoantigens with low diversity, paradoxically making them amenable to treatment with agonist of the costimulatory molecule, ICOS. These data demonstrate local environmental insults enhance TRM immunosurveillance of human tissue, shape the evolution of tumour immunogenicity and that this interplay informs effective immunotherapeutic modalities.

show abstract

The promises and challenges of early non‐small cell lung cancer detection: patient perceptions, low‐dose CT screening, bronchoscopy and biomarkers

Kalinke

¹

,

Thakrar

²

,

Janes

³

2020

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Immune Surveillance in Clinical Regression of Pre-Invasive Squamous Cell Lung Cancer

Cited by 5 publications

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Early immune pressure imposed by tissue resident memory T cells sculpts tumour evolution in non-small cell lung cancer

Early immune pressure imposed by tissue resident memory T cells sculpts tumour evolution in non-small cell lung cancer

Early immune pressure imposed by tissue resident memory T cells sculpts tumour evolution in non-small cell lung cancer

The promises and challenges of early non‐small cell lung cancer detection: patient perceptions, low‐dose CT screening, bronchoscopy and biomarkers

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