The idea that the immune system (IS) can control cancer was first proposed by P. Ehrlich at the beginning of the 20th century. Since then, many immunotherapy trials have been tested. Until recently, these treatments have proven inconclusive, tarnished by the observed collateral toxicities. The failure of vaccine therapy teaches us that the tolerogenic environment of tumors is dominant and prevents the IS from eliminating them. At the beginning of the 21st century, J. Allison and T. Honjo described the existence of negative control points of the IS corresponding among other things to the expression by T lymphocytes (TLs) of inhibitory molecules blocking their effector functions. During responses to infections, these control points restrict the activation of TLs when the pathogen is eliminated and thus prevent uncontrolled and deleterious responses. In the case of anti-tumor responses, this inhibition allows the tumor to escape the control of the IS, to grow and disseminate. Revolutionizing the management of melanoma and many other cancers, new immunotherapies targeting these negative control points, including anti-PD1 antibodies, increase patient survival. Unfortunately, only 20 to 30% of patients respond well to these treatments by developing an effective anti-tumor immune response. To overcome this insufficiency, current strategies propose to combine immunotherapy with more traditional treatments such as chemotherapy and radiotherapy. However, immunotherapy, radiotherapy and chemotherapy have harmful side effects and these toxicities can be additive or even synergistic in the case of co-treatments. It is therefore crucial to identify alternative treatments that can be combined with immunotherapies to improve their effectiveness while avoiding or limiting the occurrence of side effects.
Thanks to the results of the present study, the authors propose to increase the effectiveness of immunotherapy by increasing and directing the response of TLs by iron, a very traditional chemical element. Indeed, they observed that iron modulated metabolism and significantly increased the activation and proliferation of T cells in vitro. This “adjuvant” effect translates, in vivo, into a significant slowdown in the growth of transplanted tumor lines in mice. More specifically, these results show that iron supplementation promotes anti-cancer responses by increasing the production of anti-tumor factors by T cells and significantly improves the efficacy of anti-PD1 immunotherapy in mice. Finally, this study suggests that, in cancer patients, the quality and efficacy of the anti-tumor response following anti-PD1 immunotherapy can be modulated by the level of plasma ferritin, the concentration of which reflects the body's iron reserves.
In summary, these results suggest the benefits of iron supplementation on the reactivation of anti-tumor responses and support the relevance of combining immunotherapy and iron supplementation for the treatment of cancers.
Figure legend: The interaction between the PD1 molecule expressed on the surface of T lymphocytes and its ligand PD-L1 expressed by tumor cells leads to the inhibition of T lymphocyte effector functions and tumor escape. Immunotherapy by injection of anti-PD1 antibodies blocks this interaction and restores T cell effector functions resulting in an effective anti-tumor response. The present study suggests that iron supplementation can increase T cell responses and significantly enhance the effect of anti-PD1 immunotherapy.
Reference
Iron boosts anti-tumor type 1 T-cell responses and anti-PD1 immunotherapy. S. Porte, A. Audemard-Verger, C. Wu, A. Durand, T. Level, L. Giraud, A. Lombès, M. Germain, R. Pierre, B. Saintpierre, M. Lambert, C. Auffray, C. Peyssonnaux, F. Goldwasser, S. Vaulont, MC. Alves-Guerra, R. Dentin, B. Lucas and B. Martin. 2024. Cancer Immunology Research, July 10, 2024. doi: 10.1158/2326-6066.CIR-23-0739.
