Optimizing the Spatial Immune Landscape of CD103CD8 Tissue-resident Memory T Cells in Non-small Cell Lung Cancer by Neoadjuvant Chemotherapy

Overview

Journal Cell Oncol (Dordr)

Publisher Springer

Date 2024 Aug 19

PMID 39158668

Authors

Guanqun Yang

Mengyu Hu

Siqi Cai

Chaozhuo Li

Liying Yang

Miaoqing Zhao

Hongbiao Jing

Ligang Xing

Xiaorong Sun

Affiliations

Soon will be listed here.

Abstract

Background: Neoadjuvant chemotherapy (NAC) combined with immunotherapy is increasingly used in non-small cell lung cancer (NSCLC). Tissue-resident memory T (T) cells are the primary subset responding to anti-cancer immunity. However, the immunomodulatory effects of NAC on T cells remain unknown.

Methods: We established two NSCLC cohorts including patients undergoing upfront surgery (US) and NAC followed by surgery. Beyond the unpaired comparison between the US cohort (n = 122) and NAC cohort (n = 141) with resection samples, 58 matched pre-NAC biopsy samples were available for paired comparisons. Using multiplex immunofluorescence, we characterized T cells (CD103CD8) and four heterogeneous T subsets, including naive T (PD-1Tim-3), pre-exhausted T (PD-1Tim-3), T (PD-1Tim-3), and terminally exhausted T (PD-1Tim-3). Cell density, cytotoxicity, and two spatial features were defined to evaluate the effect of NAC on T subsets.

Results: The cell densities, infiltration scores, and cancer-cell proximity scores of T cells, especially T subsets, were significantly increased after NAC and associated with better prognosis of patients. In Contrast, no significant change was observed in the T subset, which was associated with poor prognosis. Besides, the cytotoxicity of T subsets was unaltered after NAC. Compared with patients without major pathologic response (MPRs), patients with MPR had higher densities of T subsets and higher cancer-cell proximity scores of T subsets. Furthermore, increased density of CD31 + cancer microvessels was positively associated with both T and T cells after NAC.

Conclusions: NAC may remodel the cell density and spatial distribution of T subsets, which is associated with favorable therapeutic effect and prognosis in patients with NSCLC.

References

Forde P, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad M . Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022; 386(21):1973-1985. PMC: 9844511. DOI: 10.1056/NEJMoa2202170. View

Huang M, Jiang X, Wang B, Sun Y, Lu J . Combination therapy with PD-1/PD-L1 blockade in non-small cell lung cancer: strategies and mechanisms. Pharmacol Ther. 2020; 219:107694. DOI: 10.1016/j.pharmthera.2020.107694. View

Parra E, Villalobos P, Behrens C, Jiang M, Pataer A, Swisher S . Effect of neoadjuvant chemotherapy on the immune microenvironment in non-small cell lung carcinomas as determined by multiplex immunofluorescence and image analysis approaches. J Immunother Cancer. 2018; 6(1):48. PMC: 5989476. DOI: 10.1186/s40425-018-0368-0. View

Zens P, Bello C, Scherz A, von Gunten M, Ochsenbein A, Schmid R . The effect of neoadjuvant therapy on PD-L1 expression and CD8+lymphocyte density in non-small cell lung cancer. Mod Pathol. 2022; 35(12):1848-1859. PMC: 9708547. DOI: 10.1038/s41379-022-01139-y. View

Remark R, Lupo A, Alifano M, Biton J, Ouakrim H, Stefani A . Immune contexture and histological response after neoadjuvant chemotherapy predict clinical outcome of lung cancer patients. Oncoimmunology. 2017; 5(12):e1255394. PMC: 5213838. DOI: 10.1080/2162402X.2016.1255394. View

Fu T, Dai L, Wu S, Xiao Y, Ma D, Jiang Y . Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response. J Hematol Oncol. 2021; 14(1):98. PMC: 8234625. DOI: 10.1186/s13045-021-01103-4. View

Schenkel J, Pauken K . Localization, tissue biology and T cell state - implications for cancer immunotherapy. Nat Rev Immunol. 2023; 23(12):807-823. PMC: 11448857. DOI: 10.1038/s41577-023-00884-8. View

Hombrink P, Helbig C, Backer R, Piet B, Oja A, Stark R . Programs for the persistence, vigilance and control of human CD8 lung-resident memory T cells. Nat Immunol. 2016; 17(12):1467-1478. DOI: 10.1038/ni.3589. View

Hamid M, Colin-York H, Khalid-Alham N, Browne M, Cerundolo L, Chen J . Self-Maintaining CD103 Cancer-Specific T Cells Are Highly Energetic with Rapid Cytotoxic and Effector Responses. Cancer Immunol Res. 2019; 8(2):203-216. PMC: 7611226. DOI: 10.1158/2326-6066.CIR-19-0554. View

10.

Heeg M, Goldrath A . Insights into phenotypic and functional CD8 T heterogeneity. Immunol Rev. 2023; 316(1):8-22. PMC: 10462388. DOI: 10.1111/imr.13218. View

11.

Okla K, Farber D, Zou W . Tissue-resident memory T cells in tumor immunity and immunotherapy. J Exp Med. 2021; 218(4). PMC: 7992502. DOI: 10.1084/jem.20201605. View

12.

Damei I, Trickovic T, Mami-Chouaib F, Corgnac S . Tumor-resident memory T cells as a biomarker of the response to cancer immunotherapy. Front Immunol. 2023; 14:1205984. PMC: 10399960. DOI: 10.3389/fimmu.2023.1205984. View

13.

Djenidi F, Adam J, Goubar A, Durgeau A, Meurice G, de Montpreville V . CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J Immunol. 2015; 194(7):3475-86. DOI: 10.4049/jimmunol.1402711. View

14.

Ganesan A, Clarke J, Wood O, Garrido-Martin E, Chee S, Mellows T . Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat Immunol. 2017; 18(8):940-950. PMC: 6036910. DOI: 10.1038/ni.3775. View

15.

Duhen T, Duhen R, Montler R, Moses J, Moudgil T, de Miranda N . Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun. 2018; 9(1):2724. PMC: 6045647. DOI: 10.1038/s41467-018-05072-0. View

16.

Clarke J, Panwar B, Madrigal A, Singh D, Gujar R, Wood O . Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer. J Exp Med. 2019; 216(9):2128-2149. PMC: 6719422. DOI: 10.1084/jem.20190249. View

17.

Corgnac S, Malenica I, Mezquita L, Auclin E, Voilin E, Kacher J . CD103CD8 T Cells Accumulate in Tumors of Anti-PD-1-Responder Lung Cancer Patients and Are Tumor-Reactive Lymphocytes Enriched with Tc17. Cell Rep Med. 2020; 1(7):100127. PMC: 7659589. DOI: 10.1016/j.xcrm.2020.100127. View

18.

Banchereau R, Chitre A, Scherl A, Wu T, Patil N, De Almeida P . Intratumoral CD103+ CD8+ T cells predict response to PD-L1 blockade. J Immunother Cancer. 2021; 9(4). PMC: 8032254. DOI: 10.1136/jitc-2020-002231. View

19.

van der Leun A, Thommen D, Schumacher T . CD8 T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer. 2020; 20(4):218-232. PMC: 7115982. DOI: 10.1038/s41568-019-0235-4. View

20.

Gaudreau P, Negrao M, Mitchell K, Reuben A, Corsini E, Li J . Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC. J Thorac Oncol. 2020; 16(1):127-139. PMC: 7775914. DOI: 10.1016/j.jtho.2020.09.027. View