Anti-PD1 therapies induce an early expansion of Ki67+CD8+ T cells in metastatic non-oncogene addicted NSCLC patients

Front Immunol. 2024 Dec 18:15:1483182. doi: 10.3389/fimmu.2024.1483182. eCollection 2024.

Abstract

Pembrolizumab (an anti-PD1 antibody) alone or combined with chemotherapy represented the standard of care for advanced non-oncogene addicted non-small cell lung cancer (NSCLC) patients. These therapies induced early modifications of the immune response impacting the clinical outcome. Identifying early changes in the immune system was critical to directing the therapeutic choice and improving the clinical outcome. In this study, we aim to analyze the activating and inhibiting immune cells of NSCLC patients before and during therapy to identify patients who will benefit from immunotherapies. Forty-eight NSCLC patients were analyzed before (T0) and after the first cycle of immunotherapy (T1), evaluating several activating (CD137+and PD1+), proliferating (Ki67+) and immunosuppressing immune subsets (Tregs: total, active, resting, and non-suppressive; MDSCs: PMN(Lox1+)-MDSC and M-MDSCs) by cytofluorimetry. Concurrently, 14 soluble immune checkpoints were analyzed by Luminex assay. Immunotherapy significantly increased the levels of Ki67+(total and CD8+) T cells, PMN(Lox1+)-MDSCs, non-suppressive Tregs (nsTregs), and soluble PD1 from T0 to T1 in the entire NSCLC population, while decreased active Tregs. These changes were partially attributed to responding patients who showed an increase of Ki67+ and CD8+T cells and nsTregs at T1. CD137+(total, CD8+, and CD4+) T cells and soluble LAG3 were predictor factors at T0 and T1. A low ratio of Tregs/CD137+ T cells and high levels of Ki67+CD137+ T cells positively correlated with response to therapy at T0 and T1, respectively. Results highlighted that immunotherapy improved the immunological fitness of those patients who benefited from immunotherapy, changing the immunological balance towards immune activation.

Keywords: CD137; NSCLC; anti-PD-1; immune checkpoint inhibitors; lymphocytes.

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • CD8-Positive T-Lymphocytes* / immunology
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / immunology
  • Carcinoma, Non-Small-Cell Lung* / therapy
  • Female
  • Humans
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Immunotherapy / methods
  • Ki-67 Antigen* / metabolism
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / pathology
  • Lung Neoplasms* / therapy
  • Male
  • Middle Aged
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors

Substances

  • Ki-67 Antigen
  • Programmed Cell Death 1 Receptor
  • Immune Checkpoint Inhibitors
  • Antibodies, Monoclonal, Humanized
  • PDCD1 protein, human
  • pembrolizumab
  • MKI67 protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Sapienza University of Rome (CN: RM12117A7B767D0D, RP122181610A7266, and RM123188C3F3E706; IZ: RM12117A85361029; AR: RM1221816BC0EAA; FB: RM120172B40A805A) and carried out within “Dissecting naïve PD-1 + T-cells phenotype to generate new biological insights of immunotherapy response in advanced NSCLC” (P.I. IGZ) project-funded by European Union-NextGeneration EU within the PRIN 2022 program (D.D.104–02/02/2022 Ministero dell’Università dell’Istruzione e della Ricerca). This manuscript reflects only the authors’ views and opinions, and the Ministry cannot be considered responsible for them. AA is supported by CN3 PNRR, LT and FV are supported by C_PNRR – D.M. 118 founding programs, respectively.