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      Functional status and spatial architecture of tumor-infiltrating CD8+ T cells are associated with lymph node metastases in non-small cell lung cancer

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          Abstract

          Background

          Anti-PD-(L)1 immunotherapy has been recommended for non-small cell lung cancer (NSCLC) patients with lymph node metastases (LNM). However, the exact functional feature and spatial architecture of tumor-infiltrating CD8 + T cells remain unclear in these patients.

          Methods

          Tissue microarrays (TMAs) from 279 IA-IIIB NSCLC samples were stained by multiplex immunofluorescence (mIF) for 11 markers (CD8, CD103, PD-1, Tim3, GZMB, CD4, Foxp3, CD31, αSMA, Hif-1α, pan-CK). We evaluated the density of CD8 + T-cell functional subsets, the mean nearest neighbor distance (mNND) between CD8 + T cells and neighboring cells, and the cancer-cell proximity score (CCPS) in invasive margin (IM) as well as tumor center (TC) to investigate their relationships with LNM and prognosis.

          Results

          The densities of CD8 + T-cell functional subsets, including predysfunctional CD8 + T cells (T predys) and dysfunctional CD8 + T cells (T dys), in IM predominated over those in TC ( P < 0.001). Multivariate analysis identified that the densities of CD8 + T predys cells in TC and CD8 + T dys cells in IM were significantly associated with LNM [OR = 0.51, 95%CI (0.29–0.88), P = 0.015; OR = 5.80, 95%CI (3.19–10.54), P < 0.001; respectively] and recurrence-free survival (RFS) [HR = 0.55, 95%CI (0.34–0.89), P = 0.014; HR = 2.49, 95%CI (1.60–4.13), P = 0.012; respectively], independent of clinicopathological factors. Additionally, shorter mNND between CD8 + T cells and their neighboring immunoregulatory cells indicated a stronger interplay network in the microenvironment of NSCLC patients with LNM and was associated with worse prognosis. Furthermore, analysis of CCPS suggested that cancer microvessels (CMVs) and cancer-associated fibroblasts (CAFs) selectively hindered CD8 + T cells from contacting with cancer cells, and were associated with the dysfunction of CD8 + T cells.

          Conclusion

          Tumor-infiltrating CD8 + T cells were in a more dysfunctional status and in a more immunosuppressive microenvironment in patients with LNM compared with those without LNM.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12967-023-04154-y.

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          Approaches to treat immune hot, altered and cold tumours with combination immunotherapies

          Jérôme Galon, Daniela Bruni (2019)
          Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In this Review, we focus on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and we describe approaches to treat such tumours with combination immunotherapies, including checkpoint inhibitors. In the upcoming era of combination immunotherapy, it is becoming critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity. The impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.
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            Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

            Hok Chan, Franco Verde, Haidan Guo … (2018)
            BACKGROUND Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non–small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute–Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621.)
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              Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

              Shohei Koyama, Esra A Akbay, Yvonne Y. Li … (2016)
              Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
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                Author and article information

                Contributors
                Xiaorong Sun:
                ORCID: http://orcid.org/0000-0001-8520-9556
                xrsun@sdfmu.edu.cn
                Journal
                Journal ID (nlm-ta): J Transl Med
                Journal ID (iso-abbrev): J Transl Med
                Title: Journal of Translational Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1479-5876
                Publication date (Electronic): 12 May 2023
                Publication date PMC-release: 12 May 2023
                Publication date Collection: 2023
                Volume: 21
                Electronic Location Identifier: 320
                Affiliations
                [1 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Shandong University Cancer Center, Shandong University, ; Jinan, Shandong China
                [2 ]GRID grid.440144.1, ISNI 0000 0004 1803 8437, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, ; Jinan, Shandong China
                [3 ]GRID grid.268079.2, ISNI 0000 0004 1790 6079, School of Clinical Medicine, , Weifang Medical University, ; Weifang, Shandong China
                [4 ]GRID grid.440144.1, ISNI 0000 0004 1803 8437, Shandong Cancer Hospital and Institute and Shandong Academy of Medical Science, ; Jinan, Shandong China
                [5 ]GRID grid.440144.1, ISNI 0000 0004 1803 8437, Department of Pathology, , Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, ; Jinan, Shandong China
                [6 ]GRID grid.440144.1, ISNI 0000 0004 1803 8437, Department of Radiation Oncology, , Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, ; Jinan, Shandong China
                [7 ]GRID grid.440144.1, ISNI 0000 0004 1803 8437, Department of Nuclear Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, , Shandong Cancer Hospital and Institute, ; No.440, Jiyan Road, Huaiyin District, Jinan, 250117 Shandong China
                Author information
                http://orcid.org/0000-0001-8520-9556
                Article
                Publisher ID: 4154
                DOI: 10.1186/s12967-023-04154-y
                PMC ID: 10182600
                PubMed ID: 37173705
                SO-VID: b12bdf23-b5fe-4e94-97b0-b0e48ff46b3f
                Copyright © © The Author(s) 2023
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 24 February 2023
                Date accepted : 25 April 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 82172866
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007129, Natural Science Foundation of Shandong Province;
                Award ID: ZR2021LZL005
                Award ID: ZR2019LZL019
                Award Recipient :
                Funded by: Department of Science & Technology of Shandong Province
                Award ID: 2021CXGC011102
                Award Recipient :
                Funded by: Start-up fund of Shandong Cancer Hospital
                Award ID: 2020PYA04
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © BioMed Central Ltd., part of Springer Nature 2023

                ScienceOpen disciplines: Medicine
                Keywords: cd8 + t cell,spatial architecture,dysfunction,tumor microenvironment,multiplex immunofluorescence,lung cancer
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: cd8 + t cell, spatial architecture, dysfunction, tumor microenvironment, multiplex immunofluorescence, lung cancer

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