T cells in solid tumors : investigating the immunomodulation in the tumor microenvironment

The immune system protects human from cancer through an immunosurveillance mechanism. However, the progressive nature of tumor cells to differentiate and the complexity of the tumor microenvironment may result in the immunomodulation of immune cells. In this thesis, we aim to explore the T cell immunomodulation inside the intricate solid tumor microenvironment in patients.

First, we investigated suppressive regulatory T cells (Tregs) in urinary bladder cancer (UBC). Our group previously demonstrated a contradictory finding that a high FOXP3+ tumor infiltrating lymphocyte (TIL) number correlates positively to survival. In here, we answered that FOXP3+ CD4+ T cells in the tumor were real Tregs which protectively regulated tumor invasiveness by suppressing MMP2 expression in tumor-associated macrophages (TAMs) and tumor cells. Next, we explored the subset of tissue-resident memory CD8+ T (TRM) cells from UBC tumor. It is less known whether TRM cells are effective killers of tumor cells. We revealed that tumor TRM cells were epigenetically committed to express perforin. Although TRM cells expressed exhaustion marker PD-1, they were not terminally exhausted. As a result, we found that an increased number of TRM cells in the tumor correlated with a lower tumor stage. Furthermore, we looked into the cytotoxic CD8+ T cells in the sentinel nodes (SNs) of UBC patients. Surprisingly, we discovered that SN CD8+ T cells displayed a deficiency of their cytotoxic constituent perforin, whereas granzyme B was still expressed. Thereafter, we revealed that muscle invasive UBC suppressed perforin expression using an ICAM-1/TGFβ2 – mediated pathway as an immune escape mechanism.

In the next study, we focused on the effect of standard neoadjuvant chemotherapy (NAC) and T cell responses in the SNs. We found that NAC reinforced the anti-tumor T cell activities by reducing the exhaustion in CD8+ and CD4+ effector T cells, which consequently increased their cytotoxicity and clonal expansion, respectively. Additionally, NAC also reduced the frequency and activation of the suppressive Tregs. Lastly, as a result of escaping the immune destruction, tumor can grow and metastasize. In this study, we revealed that micrometastases in lymph nodes of renal tumors could be reliably detected by flow cytometry. This method is more sensitive, objective, time- and cost-effective compared to the gold standard histopathological examination.

In conclusion, T cells are modulated in the solid tumor microenvironment. By understanding the molecular and cellular aspects of T cells in this microenvironment, we may unveil new strategies for designing cancer immunotherapies in the future.

List of scientific papers

I. Winerdal ME, Krantz D, Hartana CA, Zirakzadeh AA, Linton L, Bergman EA, Rosenblatt R, Vasko J, Alamdari F, Hansson J, Holmström B, Johansson M, Winerdal M, Marits P, Sherif A, Winqvist O. Urinary bladder cancer Tregs suppress MMP2 and potentially regulate invasiveness. Cancer Immunology Research. 2018 May; 6(5): 528-538.
https://doi.org/10.1158/2326-6066.CIR-17-0466

II. Hartana CA, Bergman EA, Broomé A, Berglund S, Johansson M, Alamdari F, Jakubczyk T, Huge Y, Aljabery F, Palmqvist K, Holmström B, Glise H, Riklund K, Sherif A, Winqvist O. Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer. Clinical and Experimental Immunology. 2018 Jul 15.
https://doi.org/10.1111/cei.13183

III. Hartana CA, Bergman EA, Zirakzadeh AA, Krantz D, Winerdal ME, Winerdal M, Johansson M, Alamdari F, Jakubczyk T, Glise H, Riklund K, Sherif A, Winqvist O. Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFβ2 mediated pathway. PLoS One. 2018 Jul 2;13(7):e0200079.
https://doi.org/10.1371/journal.pone.0200079

IV. Krantz D, Hartana CA, Winerdal ME, Johansson M, Alamdari F, Jakubczyk T, Huge Y, Aljabery F, Palmqvist K, Zirakzadeh AA, Holmström B, Riklund K, Sherif A, Winqvist O. Neoadjuvant chemotherapy reinforces antitumor T cell response in urothelial urinary bladder cancer. European Urology. 2018 Jul 16. pii: S0302-2838(18)30476-7.
https://doi.org/10.1016/j.eururo.2018.06.048

V. Hartana CA, Kinn J, Rosenblatt R, Anania S, Alamdari F, Glise H, Sherif A, Winqvist O. Detection of micrometastases by flow cytometry in sentinel lymph nodes from patients with renal tumors. British Journal of Cancer. 2016 Oct 11;115(8):957-966.
https://doi.org/10.1038/bjc.2016.279