Diversity and focus of CMV specific T-cell responses in patients post-HSCT and with solid tumor

Human Cytomegalovirus (CMV) is a beta-herpesvirus that commonly infects humans. Most symptoms in healthy individuals are very mild. The virus is never eliminated and remains in the individual life-long. Thus, CMV and the immune response stay in coexistence until the protective response remains. CMV disease occurs when the immune system is either immature or immunocompromised, such as in hematopoietic stem cell transplant recipients. Over the last decades, CMV has been reported in diverse cancer including glioblastoma (GBM) that could suggest a potential link between CMV infection and cancer initiation or development.

The papers in this thesis investigated the CMV-specific immune response of individuals in different clinical settings: patients after hematopoietic stem cell transplantation (HSCT) and patients with brain tumor or pancreatic cancer. The thesis consists of the following studies:

In Paper I, we investigated the CMV-specific interferon-gamma (IFNγ) production in a cohort of 277 patients over time post-HSCT. Impairment of the CMV-specific immune response post-HSCT is associated with CMV infection. We monitored the IFNγ production in response to CMV-pp65 over a period of 2 years post-HSCT and observed a higher IFNγ production at the first month post-HSCT. Moreover, we identified that several clinical parameters such acute graft-versus-host disease (GVHD) and CMV infection affect the IFNγ production in response to CMV-pp65.

In Paper II, we aimed to characterize the CMV-specific CD8+ cytotoxic T-cells (CTL) with high affinity T-cell receptor (TCR) in patients post-HSCT using three different CMV-pp65 tetramers. High affinity CMV-CTL presented an effector memory phenotype and a stronger PD-1 expression as compared to CMV-CTL with lower affinity. Additionally, the high affinity CMV-CTLs were found at higher proportion in patients with chronic GVHD over time post-HSCT. Therefore, Paper I and II together may better characterize the CMV-specific immune response post-HSCT and potentially the bidirectional relationship between virus and GVHD.

In Paper III, we investigated the plasma interleukin 7 (IL-7) and the soluble IL-7 receptor (sIL-7R) levels post-HSCT. IL-7, through its receptor, is essential for T-cell proliferation, thus, to the response to infection. Patients presenting CMV infection exhibited a lower plasma level of sIL-7R and higher level of IL-7 in the early months post-HSCT. Furthermore, the plasma level of IL-7R was reduced in patients with acute GVHD. Together these observations suggest that sIL-7R may be associated with increased risk of GVHD and potential CMV infection.

In Paper IV, the clinical setting is different. We focused on the CMV-specific IFNγ production in a large cohort of patients with brain tumor and pancreatic cancer. Patients with brain tumor and more specifically those with GBM presented an impaired immune response towards viral and mitogen antigens. While survival was correlated with the CMV- specific humoral response, no correlation between survival and CMV-specific IFNγ production could be observed. Contrarily, patients with high Epstein-Barr virus (EBV)- and PHA-specific IFNγ production showed an improved survival post-operation suggesting this immune response as potential marker of general immunocompetence.

List of scientific papers

I. Poiret T, Valentini D, Von Landenberg A, Liu Z Remberger M, Ringden O, Ernberg I, Ljungman P. CMV and EBV immune response characterized by specific IFN-gamma production post-HSCT correlates with grades of GVHD and CMV reactivation. [Manuscript]

II. Thomas Poiret, Rebecca Axelsson-Robertson, Mats Remberger, Xiao-Hua Luo, Martin Rao, Anurupa Nagchowdhury, Anna Von Landenberg, Ingemar Ernberg, Olle Ringden, Markus Maeurer. CMV-specific CD8+ T-cells with different TCR affinities segregate T-cell phenotypes and correlate with chronic GVHD in patients post-HSCT. Front Immunol. 2018; 9:760.
https://doi.org/10.3389/fimmu.2018.00760

III. Thomas Poiret, Lalit Rane, Mats Remberger, Birgitta Omazic, Åsa Gustafsson-Jernberg, Nalini Kumar Vudattu, Raija Ahmed, Ingemar Ernberg, Jacek Winiarski, Isabelle Magalhaes, Olle Ringden and Markus Maeurer. Reduced plasma levels of soluble interleukin-7 receptor during graft-versus-host disease (GVHD) in children and adults. BMC Immunol. 2014; 15: 25.
https://doi.org/10.1186/1471-2172-15-25

IV. Zhenjiang Liu, Thomas Poiret, Qingda Meng, Martin Rao, Anna von Landenberg, Esther Schoutrop, Davide Valentini, Ernest Dodoo, Inti-Harvey Peredo, Markus Maeurer. Epstein-Barr virus- and Cytomegalovirus-specific immune response in patients with brain cancer. J Transl Med. 2018; 16(1):182.
https://doi.org/10.1186/s12967-018-1557-9