Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC
Resident memory T cells (TRM) inhabit peripheral tissues and are critical for protection against localized infections. Recently, it has become evident that CD103+ TRM are not only important in combating secondary infections, but also for the elimination of tumor cells. In several solid cancers, intr...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02654/full |
| _version_ | 1818535347769835520 |
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| author | Anna E. Oja Berber Piet David van der Zwan Hans Blaauwgeers Mark Mensink Sander de Kivit Jannie Borst Martijn A. Nolte René A. W. van Lier Regina Stark Pleun Hombrink |
| author_facet | Anna E. Oja Berber Piet David van der Zwan Hans Blaauwgeers Mark Mensink Sander de Kivit Jannie Borst Martijn A. Nolte René A. W. van Lier Regina Stark Pleun Hombrink |
| author_sort | Anna E. Oja |
| collection | DOAJ |
| description | Resident memory T cells (TRM) inhabit peripheral tissues and are critical for protection against localized infections. Recently, it has become evident that CD103+ TRM are not only important in combating secondary infections, but also for the elimination of tumor cells. In several solid cancers, intratumoral CD103+CD8+ tumor infiltrating lymphocytes (TILs), with TRM properties, are a positive prognostic marker. To better understand the role of TRM in tumors, we performed a detailed characterization of CD8+ and CD4+ TIL phenotype and functional properties in non-small cell lung cancer (NSCLC). Frequencies of CD8+ and CD4+ T cell infiltrates in tumors were comparable, but we observed a sharp contrast in TRM ratios compared to surrounding lung tissue. The majority of both CD4+ and CD8+ TILs expressed CD69 and a subset also expressed CD103, both hallmarks of TRM. While CD103+CD8+ T cells were enriched in tumors, CD103+CD4+ T cell frequencies were decreased compared to surrounding lung tissue. Furthermore, CD103+CD4+ and CD103+CD8+ TILs showed multiple characteristics of TRM, such as elevated expression of CXCR6 and CD49a, and decreased expression of T-bet and Eomes. In line with the immunomodulatory role of the tumor microenvironment, CD8+ and CD4+ TILs expressed high levels of inhibitory receptors 2B4, CTLA-4, and PD-1, with the highest levels found on CD103+ TILs. Strikingly, CD103+CD4+ TILs were the most potent producers of TNF-α and IFN-γ, while other TIL subsets lacked such cytokine production. Whereas, CD103+CD4+PD-1low TILs produced the most effector cytokines, CD103+CD4+PD-1++ and CD69+CD4+PD-1++ TILs produced CXCL13. Furthermore, a large proportion of TILs expressed co-stimulatory receptors CD27 and CD28, unlike lung TRM, suggesting a less differentiated phenotype. Agonistic triggering of these receptors improved cytokine production of CD103+CD4+ and CD69+CD8+ TILs. Our findings thus provide a rationale to target CD103+CD4+ TILs and add co-stimulation to current therapies to improve the efficacy of immunotherapies and cancer vaccines. |
| first_indexed | 2024-12-11T18:23:39Z |
| format | Article |
| id | doaj.art-a378be8544544b5ea48cf1a77aebbab0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T18:23:39Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-a378be8544544b5ea48cf1a77aebbab02022-12-22T00:55:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-11-01910.3389/fimmu.2018.02654399954Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLCAnna E. Oja0Berber Piet1David van der Zwan2Hans Blaauwgeers3Mark Mensink4Sander de Kivit5Jannie Borst6Martijn A. Nolte7René A. W. van Lier8Regina Stark9Pleun Hombrink10Sanquin Research, Department of Hematopoiesis, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Respiratory Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, NetherlandsSanquin Research, Department of Hematopoiesis, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Pathology, Onze Lieve Vrouwe Gasthuis, Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, NetherlandsSanquin Research, Department of Hematopoiesis, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsSanquin Research, Department of Hematopoiesis, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsSanquin Research, Department of Hematopoiesis, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsSanquin Research, Department of Hematopoiesis, and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsResident memory T cells (TRM) inhabit peripheral tissues and are critical for protection against localized infections. Recently, it has become evident that CD103+ TRM are not only important in combating secondary infections, but also for the elimination of tumor cells. In several solid cancers, intratumoral CD103+CD8+ tumor infiltrating lymphocytes (TILs), with TRM properties, are a positive prognostic marker. To better understand the role of TRM in tumors, we performed a detailed characterization of CD8+ and CD4+ TIL phenotype and functional properties in non-small cell lung cancer (NSCLC). Frequencies of CD8+ and CD4+ T cell infiltrates in tumors were comparable, but we observed a sharp contrast in TRM ratios compared to surrounding lung tissue. The majority of both CD4+ and CD8+ TILs expressed CD69 and a subset also expressed CD103, both hallmarks of TRM. While CD103+CD8+ T cells were enriched in tumors, CD103+CD4+ T cell frequencies were decreased compared to surrounding lung tissue. Furthermore, CD103+CD4+ and CD103+CD8+ TILs showed multiple characteristics of TRM, such as elevated expression of CXCR6 and CD49a, and decreased expression of T-bet and Eomes. In line with the immunomodulatory role of the tumor microenvironment, CD8+ and CD4+ TILs expressed high levels of inhibitory receptors 2B4, CTLA-4, and PD-1, with the highest levels found on CD103+ TILs. Strikingly, CD103+CD4+ TILs were the most potent producers of TNF-α and IFN-γ, while other TIL subsets lacked such cytokine production. Whereas, CD103+CD4+PD-1low TILs produced the most effector cytokines, CD103+CD4+PD-1++ and CD69+CD4+PD-1++ TILs produced CXCL13. Furthermore, a large proportion of TILs expressed co-stimulatory receptors CD27 and CD28, unlike lung TRM, suggesting a less differentiated phenotype. Agonistic triggering of these receptors improved cytokine production of CD103+CD4+ and CD69+CD8+ TILs. Our findings thus provide a rationale to target CD103+CD4+ TILs and add co-stimulation to current therapies to improve the efficacy of immunotherapies and cancer vaccines.https://www.frontiersin.org/article/10.3389/fimmu.2018.02654/fullNSCLCTRMTILscytokinesexhaustiondifferentiation |
| spellingShingle | Anna E. Oja Berber Piet David van der Zwan Hans Blaauwgeers Mark Mensink Sander de Kivit Jannie Borst Martijn A. Nolte René A. W. van Lier Regina Stark Pleun Hombrink Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC Frontiers in Immunology NSCLC TRM TILs cytokines exhaustion differentiation |
| title | Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC |
| title_full | Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC |
| title_fullStr | Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC |
| title_full_unstemmed | Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC |
| title_short | Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC |
| title_sort | functional heterogeneity of cd4 tumor infiltrating lymphocytes with a resident memory phenotype in nsclc |
| topic | NSCLC TRM TILs cytokines exhaustion differentiation |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02654/full |
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