Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma.

Autor:	Davern M; Cancer 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., Donlon NE; Cancer 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., O' Connell F; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Sheppard AD; Cancer 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., Hayes C; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., King R; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Temperley H; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Butler C; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Bhardwaj A; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Moore J; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Bracken-Clarke D; Cancer 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., Donohoe C; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Ravi N; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Reynolds JV; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Maher SG; Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Conroy MJ; Cancer 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., Lysaght J; Cancer 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. Electronic address: jlysaght@tcd.ie.
Jazyk:	angličtina
Zdroj:	Translational oncology [Transl Oncol] 2022 Jun; Vol. 20, pp. 101406. Date of Electronic Publication: 2022 Mar 30.
DOI:	10.1016/j.tranon.2022.101406
Abstrakt:	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. (Copyright © 2022. Published by Elsevier Inc.)
Databáze:	MEDLINE
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