Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma
Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting ‘cold’ tumours into ‘hot’ tumours. This study profiled immune checkpoint (IC) expres...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-06-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523322000687 |
| _version_ | 1818060942529789952 |
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| author | Maria Davern Noel E. Donlon Fiona O’ Connell Andrew D. Sheppard Conall Hayes Ross King Hugo Temperley Christine Butler Anshul Bhardwaj Jenny Moore Dara Bracken-Clarke Claire Donohoe Narayanasamy Ravi John V. Reynolds Stephen G. Maher Melissa J. Conroy Joanne Lysaght |
| author_facet | Maria Davern Noel E. Donlon Fiona O’ Connell Andrew D. Sheppard Conall Hayes Ross King Hugo Temperley Christine Butler Anshul Bhardwaj Jenny Moore Dara Bracken-Clarke Claire Donohoe Narayanasamy Ravi John V. Reynolds Stephen G. Maher Melissa J. Conroy Joanne Lysaght |
| author_sort | Maria Davern |
| collection | DOAJ |
| description | Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting ‘cold’ tumours into ‘hot’ tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics. The effect of first-line chemotherapy regimens (FLOT and CROSS) on anti-tumour T cell immunity was assessed to help guide design of ICB and chemotherapy combinations in the first-line setting. The ability of ICB to enhance lymphocyte-mediated cytolysis of OAC cells in the absence and presence of post-FLOT and post-CROSS chemotherapy tumour cell secretome was assessed by a CCK-8 assay. Expression of ICs on T cells positively correlated with higher grade tumours and a subsequent poor response to neoadjuvant treatment. First-line chemotherapy regimens substantially altered IC expression profiles of T cells increasing PD-1, A2aR, KLRG-1, PD-L1, PD-L2 and CD160 and decreasing TIM-3 and LAG-3. In addition, pro-inflammatory T cell cytokine profiles were enhanced by first-line chemotherapy regimens. T cell activation status was significantly altered; both chemotherapy regimens upregulated co-stimulatory markers ICOS and CD69 yet downregulated co-stimulatory marker CD27. However, ICB attenuated chemotherapy-induced downregulation of CD27 on T cells and promoted differentiation of effector memory T cells into a terminally differentiated state. Importantly, dual nivolumab-ipilimumab treatment increased lymphocyte-mediated cytolysis of OAC cells, an effect further enhanced in the presence of post-FLOT tumour cell secretome. These findings justify a rationale to administer ICBs concurrently with first-line chemotherapies. |
| first_indexed | 2024-12-10T13:40:26Z |
| format | Article |
| id | doaj.art-c52c824c793a4acdab0d58f23a41159d |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-10T13:40:26Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-c52c824c793a4acdab0d58f23a41159d2022-12-22T01:46:42ZengElsevierTranslational Oncology1936-52332022-06-0120101406Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinomaMaria Davern0Noel E. Donlon1Fiona O’ Connell2Andrew D. Sheppard3Conall Hayes4Ross King5Hugo Temperley6Christine Butler7Anshul Bhardwaj8Jenny Moore9Dara Bracken-Clarke10Claire Donohoe11Narayanasamy Ravi12John V. Reynolds13Stephen G. Maher14Melissa J. Conroy15Joanne Lysaght16Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, IrelandCancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandCancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandCancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandDepartment of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, IrelandCancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, IrelandCancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, Ireland; Corresponding author.Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting ‘cold’ tumours into ‘hot’ tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics. The effect of first-line chemotherapy regimens (FLOT and CROSS) on anti-tumour T cell immunity was assessed to help guide design of ICB and chemotherapy combinations in the first-line setting. The ability of ICB to enhance lymphocyte-mediated cytolysis of OAC cells in the absence and presence of post-FLOT and post-CROSS chemotherapy tumour cell secretome was assessed by a CCK-8 assay. Expression of ICs on T cells positively correlated with higher grade tumours and a subsequent poor response to neoadjuvant treatment. First-line chemotherapy regimens substantially altered IC expression profiles of T cells increasing PD-1, A2aR, KLRG-1, PD-L1, PD-L2 and CD160 and decreasing TIM-3 and LAG-3. In addition, pro-inflammatory T cell cytokine profiles were enhanced by first-line chemotherapy regimens. T cell activation status was significantly altered; both chemotherapy regimens upregulated co-stimulatory markers ICOS and CD69 yet downregulated co-stimulatory marker CD27. However, ICB attenuated chemotherapy-induced downregulation of CD27 on T cells and promoted differentiation of effector memory T cells into a terminally differentiated state. Importantly, dual nivolumab-ipilimumab treatment increased lymphocyte-mediated cytolysis of OAC cells, an effect further enhanced in the presence of post-FLOT tumour cell secretome. These findings justify a rationale to administer ICBs concurrently with first-line chemotherapies.http://www.sciencedirect.com/science/article/pii/S1936523322000687PD-1A2aRCTLA-4FLOT regimenCROSS regimen |
| spellingShingle | Maria Davern Noel E. Donlon Fiona O’ Connell Andrew D. Sheppard Conall Hayes Ross King Hugo Temperley Christine Butler Anshul Bhardwaj Jenny Moore Dara Bracken-Clarke Claire Donohoe Narayanasamy Ravi John V. Reynolds Stephen G. Maher Melissa J. Conroy Joanne Lysaght Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma Translational Oncology PD-1 A2aR CTLA-4 FLOT regimen CROSS regimen |
| title | Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma |
| title_full | Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma |
| title_fullStr | Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma |
| title_full_unstemmed | Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma |
| title_short | Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma |
| title_sort | cooperation between chemotherapy and immune checkpoint blockade to enhance anti tumour t cell immunity in oesophageal adenocarcinoma |
| topic | PD-1 A2aR CTLA-4 FLOT regimen CROSS regimen |
| url | http://www.sciencedirect.com/science/article/pii/S1936523322000687 |
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