Multiomic analysis of T cells in response to cancers and microbes

The human immune system consists of various cell subsets, cytokines and their interactions. Traditionally researchers focus on one compartment at a time, however, with the advance in high-throughput, multi-omics techniques, it is possible to monitor multiple compartments of the immune system simultaneously. Systems immunology is then proposed and provide a broader perspective of the immune landscape. This thesis will investigate the human immune responses against cancers and microbes with a focus on T cells using systems-level immunomonitoring.

In paper I, we recruited a pan-cancer cohort of patients with pediatric solid tumors and performed systems-level immunomonitoring. We found that tumor type and age of patient have balanced contributions to the immune responses against tumor. The T cell clonal expansion is rare prior to treatment but can be elicited by treatments. Those clonally expanded T cells, although less abundant in children, are transcriptionally comparable to those in adults with more immunogenic cancers. This study demonstrated the possibility for precision immunotherapies for children with cancer.

In paper II, we studied the immune development of the extremely preterm infants. We described a delayed immune normalization in the most immature infants with gestational age 22-24 weeks, but they follow the similar trajectory as indicated by term controls. We also demonstrated a strong influence of motherŐs own milk, but not pasteurized donor milk, in promoting healthy immune development comparable to healthy term infants. The different immune developments in infants fed with motherŐs own milk and donor milk are manifested by NK cell development. Neither of the differences can be explained by microbiome composition, indicating direct effects of bioactive components in motherŐs own milk.

In paper III, we demonstrated that a deficiency of bifidobacteria, particularly the depletion of genes essential for human milk oligosaccharide (HMO) utilization in the metagenome, is linked to systemic inflammation and immune dysregulation in early life. In breastfed infants supplemented with Bifidobacterium infantis (B.infantis), which possesses all HMO-utilization genes, intestinal Th2 and Th17 cytokines were suppressed while IFN-_ was induced. Fecal water from B.infantis-supplemented infants contained abundant indolelactate (ILA) and indole-3-lactic acid, which upregulated immunoregulatory galectin-1 in Th2 and Th17 cells and induced a skewed Th1 polarization. This provides a functional connection between beneficial microbes and immunoregulation during the first months of life.

In paper IV, we studied acute COVID-19 patients with longitudinal immunomonitoring and found an immune trajectory from admission to recovery that is shared in those patients. We also described an IFN_-eosinophil axis activated right before lung hyperinflammation.

In paper V, we investigated severe long COVID patients with organ damage or dysfunction. By performing systems-level immunomonitoring, we identified elevated serological responses to SARS-CoV-2 in severe Long COVID, indicative of chronic antigen stimulation. Elevated serologic responses to SARS-CoV-2 were inversely correlated with clonally expanded memory CD8+ T cells with specificity to SARS-CoV-2. This suggests that restrained SARS-CoV-2-specific clonal expansion enables viral persistence, chronic antigen exposure, and elevated IgG responses.

List of scientific papers

I. Systems-level immunomonitoring in children with solid tumors. Chen, Q.*, Zhao, B.*, Tan, Z.*, Hedberg, G., Wang, J., Gonzalez, L., Mugabo, C. H., Johnsson, A., Pi–ero P‡ez, L., Rodriguez, L., James, A., Chen, Y., Mikes, J., Barcenilla, H., Wang, C., Davis, M. M., Carlson, L.-M., Pal, N., Herold, N., Blomgren, K., Repsilber, D., Lakshmikanth, T., Kogner, P., Ljungblad, L.*, Brodin, P. [Manuscript]

II. MothersŐ own milk normalize immune system development in extremely preterm infants. Tan, Z.*, Zhong, W.*, Danielsson, H., Arzoomand, A., Lakshmikanth, T., Chen, Q., Mikes, J., Wang, J., Chen, Y., James, A., Nilsson, A. K., Elfvin, A., Brusselaers, N., Portlock, T., Lundgren, P., SŠvman, K., Wackernagel, D., Hansen-Pupp, I., Ley, D., UhlŽn, M., Hellstršm, A., Brodin, P. [Manuscript]

III. Bifidobacteria-mediated immune system imprinting early in life. Henrick, B. M.*, Rodriguez, L., Lakshmikanth, T., Pou, C., Henckel, E., Arzoomand, A., Olin, A., Wang, J., Mikes, J., Tan, Z., Chen, Y., Ehrlich, A. M., Bernhardsson, A. K., Mugabo, C. H., Ambrosiani, Y., Gustafsson, A., Chew, S., Brown, H. K., Prambs, J., Bohlin, K., Mitchell, R. D., Underwood, M. A., Smilowitz, J. T., German, J. B., Frese, S. A., Brodin, P. Cell. 184, 3884Đ3898.e11, (2021).
https://doi.org/10.1016/j.cell.2021.05.030

IV. Systems-Level Immunomonitoring from Acute to Recovery Phase of Severe COVID-19. Rodriguez, L.*, Pekkarinen, P. T.*, Lakshmikanth, T.*, Tan, Z.*, Consiglio, C. R.*, Pou, C., Chen, Y., Mugabo, C. H., Nguyen, N. A., Nowlan, K., Strandin, T., Levanov, L., Mikes, J., Wang, J., Kantele, A., Hepojoki, J., Vapalahti, O., Heinonen, S., KekŠlŠinen, E., Brodin, P. Cell Reports Medicine. 1, 100078, (2020).
https://doi.org/10.1016/j.xcrm.2020.100078

V. Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID. Rodriguez, L.*, Tan, Z.*, Lakshmikanth, T., Wang, J., Barcenilla, H., Swank, Z., Zuo, F., Abolhassani, H., Pavlovitch-Bedzyk, A. J., Wang, C., Gonzalez, L., Mugabo, C. H., Johnsson, A., Chen, Y., James, A., Mikes, J., Kleberg, L., Sundling, C., Bjšrnson, M., Nygren Bonnier, M., StŚhlberg, M., Runold, M., Bjšrkander, S., MelŽn, E., Meyts, I., Van Weyenbergh, J., Hammarstršm, Q.-P., Davis, M. M., Walt, D. R., Landegren, N., COVID Human Genetic Effort, Aiuti, A., Casari, G., Casanova, J.-L., Jamoulle, M., Bruchfeld, J., Brodin, P. [Manuscript]