Tumor-induced immune dysfunction : mechanism and therapeutic strategies

Cancer is one of the major causes of premature death in humans. Although standard treatments, such as surgery and chemotherapy, are successful in many cases, there are instances when their utility and efficacy are limited. Immunotherapy against cancer has recently been developed as an example of a new generation of gtargeted h therapy. However, the immunosuppressive milieu associated with tumors is an obstacle that needs to be overcome to improve the response rates of immunotherapeutic approaches.

Several biological processes are involved in the induction and resolution of an immune response and these need to be in perfect equilibrium to allow optimal functioning of the immune system. However, this balance is skewed in cancer patients creating a state of chronic inflammation that in turn results in a suppression of the immune system leading to tumor ]induced immune dysfunction. Several mechanisms have been suggested to contribute to this phenomenon, including mechanisms that induce oxidative stress in cancer patients.

The aim of this thesis is to elucidate the effects of oxidative stress on lymphocytes and define methods of reducing it. We have shown that oxidative stress affects competent anti ]tumor cells, such as CD8+ T effector memory cells and CD56dim NK cells, most as compared to other cells in the immune system. This may provide one explanation for the limited clinical response noted with active immunotherapy against cancer. To counteract oxidative stress, we have developed two approaches; firstly, we have been able to increase NK cell function in cancer patients by oral administration of the antioxidant vitamin E. Secondly, by transferring a gene encoding for the antioxidant enzyme catalase we were able to increase the antioxidant capacity in lymphocytes and improve their ability to resist oxidative stress.

The work performed within this thesis furthers the understanding of oxidative stress ]induced suppression of lymphocytes. This study has also contributed to the development of approaches for reversing this suppression. Methods for reversing oxidative stress ]induced immune dysfunction may potentially improve the clinical outcome of subsequent active immunotherapy regimens against cancer.

List of scientific papers

I. Takahashi A, Hanson MG, Norell HR, Havelka AM, Kono K, Malmberg KJ, Kiessling RV (2005). "Preferential cell death of CD8+ effector memory (CCR7-CD45RA-) T cells by hydrogen peroxide-induced oxidative stress." J Immunol 174(10): 6080-7
https://pubmed.ncbi.nlm.nih.gov/15879102

II. Harlin H, Hanson M, Johansson CC, Sakurai D, Poschke I, Norell H, Malmberg KJ, Kiessling R (2007). "The CD16- CD56(bright) NK cell subset is resistant to reactive oxygen species produced by activated granulocytes and has higher antioxidative capacity than the CD16+ CD56(dim) subset."
https://pubmed.ncbi.nlm.nih.gov/17878347

III. Hanson MG, Ozenci V, Carlsten MC, Glimelius BL, Frödin JE, Masucci G, Malmberg KJ, Kiessling RV (2007). "A short-term dietary supplementation with high doses of vitamin E increases NK cell cytolytic activity in advanced colorectal cancer patients." Cancer Immunol Immunother 56(7): 973-84. Epub 2006 Dec 2
https://pubmed.ncbi.nlm.nih.gov/17143612

IV. Hanson M, Mimura K, Larsson C, Palma T, Sakurai D, Norell H, Li M, Nishimura M, Kiessling R (2007). "Transduction with the antioxidant enzyme catalase protects human T cells against oxidative stress." (Submitted)