Impaired Cytolytic Activity and Loss of Clonal Neoantigens in Elderly Patients With Lung Adenocarcinoma
Open accessAbstract
Introduction Whether the efficacy of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors declines with senescence remains controversial for lung adenocarcinoma (LUAD). Responsiveness to anti-PD-1/PD-L1 therapy is thought to rely on neoantigen exposure and immune elements in the tumor microenvironment. In this study, we explored the features of the tumor immune microenvironment in elderly patients with treatment-naïve LUAD.Methods Transcriptome profiles and clinical characteristics of patients with LUAD were retrieved from The Cancer Genome Atlas as a discovery cohort. Immune cell infiltration (quantified by a single-sample gene set enrichment analysis), immunoregulatory molecule expression, and mutational patterns (from The Cancer Immunome Atlas) were compared between young and elderly patients. Immune cell infiltration was verified by immunohistochemistry using a validation cohort including 105 treatment-naïve patients with LUAD. A tissue microarray consisting of 120 LUAD patients was used in the immunohistochemistry validation.Results Activated CD8+ T cell numbers increased slightly with age, but cytolytic molecules in T cells (granzyme B [GZMB], perforin 1 [PRF1], granzyme A [GZMA], granzyme M [GZMM], and granulysin [GNLY]) gradually declined. PD-L1 expression was not associated with age; however, a number of immunosuppressive elements beyond PD-L1 were upregulated in aging patients, including regulatory T cells and co-inhibitory molecules, for example, TIM-3, TIGIT, and HHLA2. Finally, senescence was accompanied by a loss of clonal neoantigens, which is believed to be correlated with responsiveness to immune checkpoint inhibitors.Conclusions Elderly patients were characterized by increased numbers of CD8+ T cells and impaired cytolytic molecule expression. The observed immune signature was also associated with a loss of clonal neoantigens and the accumulation of immunosuppressive elements. These findings show a unique immune microenvironment in senescence and support biomarker-guided candidate identification for anti-PD-1/PD-L1 therapeutic strategies for elderly patients with LUAD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In Lewis lung cancer mouse models and patients with lung cancer, Treg infiltration and Foxp3 mRNA expression levels were higher in the elderly group than in the younger group.
“Similarly, in Lewis lung cancer mouse models and patients with lung cancer, Tregs infiltration and Foxp3 mRNA expression levels were higher in the elderly group than in the younger group [135, 136].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [136]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer
Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A., Gottfried, M., Peled, N., Tafreshi, A., Cuffe, S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1606774 · Cited by 10,089 · see citing works
Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D. R., Steins, M., Ready, N. E., Chow, L. Q., Vokes, E. E., Felip, E., Holgado, E., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1507643 · Cited by 9,335 · see citing works
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer
Brahmer, J., Reckamp, K. L., Baas, P., Crinò, L., Eberhardt, W. E. E., Poddubskaya, E., Antonia, S., Pluzanski, A., Vokes, E. E., Holgado, E., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504627 · Cited by 8,447 · see citing works
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., et al. (2014) · Nature · doi:10.1038/nature13954 · Cited by 6,609 · see citing works
Herbst, R. S., Baas, P., Kim, D.-W., Felip, E., Pérez-Gracia, J. L., Han, J.-Y., Molina, J., Kim, J.-H., Arvis, C. D., Ahn, M.-J., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01281-7 · Cited by 6,449 · see citing works
Comprehensive molecular profiling of lung adenocarcinoma
The Cancer Genome Atlas Research Network (2014) · Nature · doi:10.1038/nature13385 · Cited by 5,732 · see citing works
Charoentong, P., Finotello, F., Angelova, M., Mayer, C., Efremova, M., Rieder, D., Hackl, H., & Trajanoski, Z. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.019 · Cited by 5,041 · see citing works
Rittmeyer, A., Barlési, F., Waterkamp, D., Park, K., Ciardiello, F., von Pawel, J., Gadgeel, S. M., Hida, T., Kowalski, D. M., Cobo, M., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)32517-x · Cited by 4,684 · see citing works
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., et al. (2009) · Nature · doi:10.1038/nature08460 · Cited by 3,869 · see citing works
Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden
Chalmers, Z. R., Connelly, C. F., Fabrizio, D., Gay, L., Ali, S. M., Ennis, R., Schrock, A., Campbell, B., Shlien, A., Chmielecki, J., et al. (2017) · Genome Medicine · doi:10.1186/s13073-017-0424-2 · Cited by 3,519 · see citing works
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
McGranahan, N., Furness, A. J. S., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S. K., Jamal-Hanjani, M., Wilson, G. A., Birkbak, N. J., Hiley, C. T., et al. (2016) · Science · doi:10.1126/science.aaf1490 · Cited by 3,065 · see citing works
First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer
Carbone, D. P., Reck, M., Paz-Ares, L., Creelan, B., Horn, L., Steins, M., Felip, E., van den Heuvel, M. M., Ciuleanu, T.-E., Badin, F., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1613493 · Cited by 2,503 · see citing works
Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers
Goodman, A. M., Kato, S., Bazhenova, L., Patel, S. P., Frampton, G. M., Miller, V., Stephens, P. J., Daniels, G. A., & Kurzrock, R. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0386 · Cited by 2,264 · see citing works
Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing
Imielinski, M., Berger, A. H., Hammerman, P. S., Hernandez, B., Pugh, T. J., Hodis, E., Cho, J., Suh, J., Capelletti, M., Sivachenko, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.08.029 · Cited by 1,789 · see citing works
Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent
Kamphorst, A. O., Wieland, A., Nasti, T., Yang, S., Zhang, R., Barber, D. L., Konieczny, B. T., Daugherty, C. Z., Koenig, L., Yu, K., et al. (2017) · Science · doi:10.1126/science.aaf0683 · Cited by 1,015 · see citing works
A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing
Pan, D., Kobayashi, A., Jiang, P., Ferrari de Andrade, L., Tay, R. E., Luoma, A. M., Tsoucas, D., Qiu, X., Lim, K., Rao, P., et al. (2018) · Science · doi:10.1126/science.aao1710 · Cited by 852 · see citing works
The head and neck cancer immune landscape and its immunotherapeutic implications
Mandal, R., Şenbabaoğlu, Y., Desrichard, A., Havel, J. J., Dalin, M. G., Riaz, N., Lee, K.-W., Ganly, I., Hakimi, A. A., Chan, T. A.-T., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.89829 · Cited by 765 · see citing works
Programmed death ligand-1 expression in non-small cell lung cancer
Velcheti, V., Schalper, K. A., Carvajal, D. E., Anagnostou, V., Syrigos, K. N., Sznol, M., Herbst, R. S., Gettinger, S. N., Chen, L., & Rimm, D. L. (2013) · Laboratory Investigation · doi:10.1038/labinvest.2013.130 · Cited by 752 · see citing works
Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity
Overacre-Delgoffe, A. E., Chikina, M., Dadey, R. E., Yano, H., Brunazzi, E. A., Shayan, G., Horne, W., Moskovitz, J. M., Kolls, J. K., Sander, C., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.005 · Cited by 627 · see citing works
Angelova, M., Charoentong, P., Hackl, H., Fischer, M. L., Snajder, R., Krogsdam, A., Waldner, M. J., Bindea, G., Mlecnik, B., Galon, J., et al. (2015) · Genome biology · doi:10.1186/s13059-015-0620-6 · Cited by 521 · see citing works
The determinants of tumour immunogenicity
Blankenstein, T. J. F., Coulie, P. G., Gilboa, E., & Jaffee, E. M. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3246 · Cited by 437 · see citing works
Horikawa, N., Abiko, K., Matsumura, N., Hamanishi, J., Baba, T., Yamaguchi, K. D., Yoshioka, Y., Koshiyama, M., & Konishi, I. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0387 · Cited by 276 · see citing works
Hakim, F. T., Flomerfelt, F. A., Boyiadzis, M. M., & Gress, R. E. (2004) · Current Opinion in Immunology · doi:10.1016/j.coi.2004.01.009 · Cited by 272 · see citing works
The prognostic value of PD-L1 expression for non-small cell lung cancer patients: A meta-analysis
Wang, A., Wang, H. Y., Liu, Y., Zhao, M. C., Zhang, H., Lu, Z., Fang, Y. C., Chen, X., & Liu, G. T. (2015) · European Journal of Surgical Oncology · doi:10.1016/j.ejso.2015.01.020 · Cited by 255 · see citing works
Sun, J., Zhou, W., Choi, Y., Choi, S., Kim, S. E., Wang, Z., Dolled-Filhart, M. P., Emancipator, K., Wu, D., WEINER, R. S., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.04.007 · Cited by 152 · see citing works
Domingo, E., Camps, C., Kaisaki, P. J., Parsons, M. J., Mouradov, D., Pentony, M. M., Makino, S., Palmieri, M., Ward, R. L., Hawkins, N. J., et al. (2018) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(18)30117-1 · Cited by 76 · see citing works
Jin, Y., Zhang, P., Li, J., Zhao, J., Liu, C., Yang, F., Yang, D., Gao, A., Lin, W., Ma, X., et al. (2015) · PubMed Central · Cited by 70 · see citing works
Intratumoral Immune Cell Densities Are Associated with Lung Adenocarcinoma Gene Alterations
Mansuet‐Lupo, A., Alifano, M., Pécuchet, N., Biton, J., Becht, É., Goc, J., Germain, C., Ouakrim, H., Régnard, J., Cremer, I., et al. (2016) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201510-2031oc · Cited by 67 · see citing works
Blomberg, B. B., Frasca, D., Diaz, A., & Antoni, M. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.210.supp.88.13 · Cited by 45 · see citing works
Scott, D. W., & Steidl, C. (2014) · Hematology · doi:10.1182/asheducation-2014.1.144 · Cited by 44 · see citing works
Mutational load and mutational patterns in relation to age in head and neck cancer
Meucci, S., Keilholz, U., Tinhofer, I., & Ebner, O. A. (2016) · Oncotarget · doi:10.18632/oncotarget.11312 · Cited by 29 · see citing works
Cui, S., Dong, L., Qian, J., Lin, Y., & Jiang, L. (2017) · Journal of Cancer · doi:10.7150/jca.21842 · Cited by 12 · see citing works
Resistance of Cancer Cells to CTL-Mediated Immunotherapy
Bonavida, B., & Chouaı̈b, S. (2015) · Resistance to targeted anti-cancer therapeutics · doi:10.1007/978-3-319-17807-3 · Cited by 7 · see citing works
Interferon-gamma induces PD-L1 expression in macrophages and neutrophils
Chung, B., De, M., De, A. K., et al. (2011) · Journal of the American College of Surgeons · doi:10.1016/j.jamcollsurg.2011.06.141 · Cited by 4 · see citing works
Role of Co-inhibitory Molecules in Tumor Escape from CTL Attack
Norde, W. J., Hobo, W. A., & Dolstra, H. (2015) · Resistance to targeted anti-cancer therapeutics · doi:10.1007/978-3-319-17807-3_2 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Immunosenescence: a key player in cancer development
Lian, J., Yue, Y., Yu, W., & Zhang, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00986-z · Cited by 510 · see citing works
- Authors
- Gong, Z., Jia, Q., Chen, J., Diao, X., Gao, J., Wang, X., & Zhu, B.
- Affiliations
- Army Medical University (CN)
- Corresponding author
- Zhu, Bo
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 14
- Issue
- 5
- Pages
- 857-866
- ISSN
- 1556-0864 (ISSN-L)
- OpenAlex
- W2913044430
- Cited by
- 43
- References
- 35
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 8
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Aerospace Science Foundation of China (81620108023, 81222031, 81472648)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- lung adenocarcinoma, aging, immunosenescence, cytolytic activity, T cell cytotoxicity, PD-L1, PD-1/PD-L1 inhibitors, tumor immune microenvironment, immune cell infiltration, regulatory T cells, co-inhibitory molecules, TIM-3, TIGIT, HHLA2, granzyme B, perforin, immunotherapy response biomarkers
- MeSH terms
- Adenocarcinoma of Lung, Age Factors, Aged, Aged, 80 and over, Antigens, Neoplasm, Female, Humans, Immunotherapy, Lung Neoplasms, Male, Cohort Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
