Abstract

Checkpoint inhibitor drugs, anti-PD1 and anti-LAG3, aim to reinvigorate the immune response of CD8+ T cells against tumors. However, their effects on other immune cells like natural killer (NK) and NKT cells, as well as the varying patient responses, remain unclear. This doctoral research aimed to study the effects of checkpoint inhibitors on melanoma patients' immune system, while also seeking biomarkers for therapy response. In study I, we analyzed peripheral blood (PB) and tumor samples of metastatic melanoma patients treated with anti-PD1. The results indicated that the frequency of NKT cells, CD25+ and CD45RO+ cytotoxic NK cells, and serum CXC chemokines increased significantly in responders. The baseline predictors of treatment response included age-associated biological characteristics. In study II, we developed a bioinformatic tool to identify tumor peptides resembling viral epitopes and showed their ability to enhance cancer immunotherapy effectiveness in mice. In melanoma patients receiving anti-PD1, high CMV-specific antibody levels correlated with extended progression-free survival, and their immune cells exhibited potential reactivity to both melanoma and CMV peptides. Further, T cell receptor (TCR) sequencing identified the expansion of the same CD8+ T cell clones in response to specific tumor and viral peptides. In study III, we analyzed PB samples from immuno-oncology naïve or refractory metastatic melanoma patients treated with anti-LAG3+anti-PD1 therapy. The results indicated that NK cells, regulatory T cells, and CD8+ T cells had the highest LAG3 expression and significant changes during treatment. Responders had higher baseline TCR clonality, enriched adaptive NK cells that became activated during treatment, and their expanding CD8+ T-cell clones gained a more cytotoxic NK-like phenotype. In study IV, we analyzed melanoma patients' CD56+ lymphocytes from paired tumor and PB samples. The results suggested enrichment in cytokine stimulus and IFN-γ signaling in the tumor infiltrating NK and NKT cells. Also, many T cell clones identified in PB CD56+ lymphocytes were present in tumor samples, with some predicted to target melanoma-associated antigens. In conclusion, this thesis reveals that immune checkpoint inhibitors have profound effects on various immune cells, enhancing the antitumor potential of NK and NKT cells and altering cytokine stimulus for an improved antitumor immune response. Potential biomarkers of favorable therapy response were identified, warranting further investigation in larger clinical trials. Additionally, the findings highlight the influence of cross-reacting T-cells and pre-existing immunity on immunotherapy response.
Original languageEnglish
Supervisors/Advisors
  • Mustjoki, Satu, Supervisor
  • Kreutzman, Anna, Supervisor
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-9496-1
Electronic ISBNs978-951-51-9497-8
Publication statusPublished - 2023
MoE publication typeG5 Doctoral dissertation (article)

Bibliographical note

M1 - 88 s. + liitteet

Fields of Science

  • 3122 Cancers
  • 3111 Biomedicine

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