Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3
Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma conc...
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| Format: | Article |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1097309/full |
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| author | Bernardo L. Rapoport Bernardo L. Rapoport Bernardo L. Rapoport Helen C. Steel Carol A. Benn Carol A. Benn Simon Nayler Simon Nayler Teresa Smit Liezl Heyman Annette J. Theron Nomsa Hlatshwayo Nomsa Hlatshwayo Luyanda L.I. Kwofie Luyanda L.I. Kwofie Pieter W.A. Meyer Pieter W.A. Meyer Ronald Anderson |
| author_facet | Bernardo L. Rapoport Bernardo L. Rapoport Bernardo L. Rapoport Helen C. Steel Carol A. Benn Carol A. Benn Simon Nayler Simon Nayler Teresa Smit Liezl Heyman Annette J. Theron Nomsa Hlatshwayo Nomsa Hlatshwayo Luyanda L.I. Kwofie Luyanda L.I. Kwofie Pieter W.A. Meyer Pieter W.A. Meyer Ronald Anderson |
| author_sort | Bernardo L. Rapoport |
| collection | DOAJ |
| description | Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma concentrations of 16 soluble co-stimulatory and co-inhibitory, immune checkpoints were measured sequentially in a cohort of newly diagnosed, early BC patients (n=72), pre-treatment, post-NAC and post-surgery using a Multiplex® bead array platform. Relative to a group of healthy control subjects (n=45), the median pre-treatment levels of five co-stimulatory (CD27, CD40, GITRL, ICOS, GITR) and three co-inhibitory (TIM-3, CTLA-4, PD-L1) soluble checkpoints were significantly lower in the BC patients vs. controls (p<0.021-p<0.0001; and p<0.008-p<0.00001, respectively). Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in activation of CD8+ cytotoxic T cells, were significantly increased (p<0.04-p<0.00001), comparable with control values and remained at these levels post-surgery. Of the soluble co-inhibitory checkpoints, three (LAG-3, PD-L1, TIM-3) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p<0.03 and p<0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints is seemingly indicative of reversal of systemic immune dysregulation following administration of NAC in early BC, while recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. Although a pathological complete response (pCR) was documented in 61% of patients (mostly triple-negative BC), surprisingly, none of the soluble immune checkpoints correlated with the pCR, either pre-treatment or post-NAC. Nevertheless, in the case of the co-stimulatory ICMs, these novel findings are indicative of the immune-restorative potential of NAC in early BC, while in the case of the co-inhibitory ICMs, elevated levels of soluble PD-L1, LAG-3 and TIM-3 post-NAC underscore the augmentative immunotherapeutic promise of targeting these molecules, either individually or in combination, as a strategy, which may contribute to the improved management of early BC. |
| first_indexed | 2024-04-09T20:37:07Z |
| format | Article |
| id | doaj.art-c0d832b8aaf346e1977b95024d31c946 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-09T20:37:07Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-c0d832b8aaf346e1977b95024d31c9462023-03-30T07:56:18ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-03-011310.3389/fonc.2023.10973091097309Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3Bernardo L. Rapoport0Bernardo L. Rapoport1Bernardo L. Rapoport2Helen C. Steel3Carol A. Benn4Carol A. Benn5Simon Nayler6Simon Nayler7Teresa Smit8Liezl Heyman9Annette J. Theron10Nomsa Hlatshwayo11Nomsa Hlatshwayo12Luyanda L.I. Kwofie13Luyanda L.I. Kwofie14Pieter W.A. Meyer15Pieter W.A. Meyer16Ronald Anderson17Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaMedical Oncology Centre of Rosebank, Johannesburg, South AfricaNetcare Breast Care Centre, Johannesburg, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaNetcare Breast Care Centre, Johannesburg, South AfricaDepartment of Surgery, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaNetcare Breast Care Centre, Johannesburg, South AfricaDrs Gritzman & Thatcher Inc. Laboratories, University of the Witwatersrand Donald Gordon Medical Centre, Johannesburg, South AfricaMedical Oncology Centre of Rosebank, Johannesburg, South AfricaMedical Oncology Centre of Rosebank, Johannesburg, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDepartment of Immunology, Tshwane Academic Division of the National Health Laboratory Service, Pretoria, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDepartment of Immunology, Tshwane Academic Division of the National Health Laboratory Service, Pretoria, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaDepartment of Immunology, Tshwane Academic Division of the National Health Laboratory Service, Pretoria, South AfricaDepartment of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaNeoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma concentrations of 16 soluble co-stimulatory and co-inhibitory, immune checkpoints were measured sequentially in a cohort of newly diagnosed, early BC patients (n=72), pre-treatment, post-NAC and post-surgery using a Multiplex® bead array platform. Relative to a group of healthy control subjects (n=45), the median pre-treatment levels of five co-stimulatory (CD27, CD40, GITRL, ICOS, GITR) and three co-inhibitory (TIM-3, CTLA-4, PD-L1) soluble checkpoints were significantly lower in the BC patients vs. controls (p<0.021-p<0.0001; and p<0.008-p<0.00001, respectively). Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in activation of CD8+ cytotoxic T cells, were significantly increased (p<0.04-p<0.00001), comparable with control values and remained at these levels post-surgery. Of the soluble co-inhibitory checkpoints, three (LAG-3, PD-L1, TIM-3) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p<0.03 and p<0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints is seemingly indicative of reversal of systemic immune dysregulation following administration of NAC in early BC, while recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. Although a pathological complete response (pCR) was documented in 61% of patients (mostly triple-negative BC), surprisingly, none of the soluble immune checkpoints correlated with the pCR, either pre-treatment or post-NAC. Nevertheless, in the case of the co-stimulatory ICMs, these novel findings are indicative of the immune-restorative potential of NAC in early BC, while in the case of the co-inhibitory ICMs, elevated levels of soluble PD-L1, LAG-3 and TIM-3 post-NAC underscore the augmentative immunotherapeutic promise of targeting these molecules, either individually or in combination, as a strategy, which may contribute to the improved management of early BC.https://www.frontiersin.org/articles/10.3389/fonc.2023.1097309/fullbreast cancerco-inhibitory checkpointsco-stimulatory checkpointscytotoxic T cellsimmunotherapyimmune dysregulation |
| spellingShingle | Bernardo L. Rapoport Bernardo L. Rapoport Bernardo L. Rapoport Helen C. Steel Carol A. Benn Carol A. Benn Simon Nayler Simon Nayler Teresa Smit Liezl Heyman Annette J. Theron Nomsa Hlatshwayo Nomsa Hlatshwayo Luyanda L.I. Kwofie Luyanda L.I. Kwofie Pieter W.A. Meyer Pieter W.A. Meyer Ronald Anderson Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3 Frontiers in Oncology breast cancer co-inhibitory checkpoints co-stimulatory checkpoints cytotoxic T cells immunotherapy immune dysregulation |
| title | Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3 |
| title_full | Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3 |
| title_fullStr | Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3 |
| title_full_unstemmed | Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3 |
| title_short | Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3 |
| title_sort | dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of cd27 cd28 cd40 cd80 icos and gitr and substantially increased levels of pd l1 lag 3 and tim 3 |
| topic | breast cancer co-inhibitory checkpoints co-stimulatory checkpoints cytotoxic T cells immunotherapy immune dysregulation |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1097309/full |
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