Stimulating the immune system: an effective anti-cancer tool.

Immune therapy is gaining increasing attention as a valuable tool to eliminate cancer cells. The founding principle is that the patient’s immune system can be properly stimulated to recognize cancer cells as foreign, like microbes, and remove them by phagocytosis.

Mechanism of anti-tumoral macrophage activity. Macrophages are effector cells having a main role in the phagocytic process. Their action is dampened by parallel mechanisms: one mechanism is mediated by the interaction of a protein named SIRPalpha on the surface of macrophages and a protein named CD47 expressed on the surface of cancer cells; another mechanism is mediated by the interaction between LILRB1 protein expressed on macrophages’ surface and the protein complex MHC I. Both mechanisms represent “don't eat me” signals exposed by the cell preventing phagocytosis by macrophages.

An interesting point to highlight is that MHC I/LILRB1 protein interaction has been already described in T cells (another subtype of the immune system), but, differently from macrophages, in this case MHC I is required for T cell activation (see https://archive-sciencewhatelse.jimdo.com/immune-system/) against microbial infection.

Cancer cells normally have a reduced MHC I expression; therefore, on one side T cells’ activation against them is reduced, whereas in parallel, by downregulating a “don't eat me signal”, MHC I reduced expression results into macrophage activation and phagocytosis of cancer cells: macrophages acquire an anti-tumor phenotype.

What is the implication of unveiling this mechanism for immune therapy? Being already more sensitive (due to their low MHC I expression) to phagocytosis by macrophages, cancer cells appear to be a better target for macrophage-mediated immune therapy rather than T cell-mediated therapy.

Furthermore, quantification of MHC expression might represent a mark to predict the low efficacy of T cells-mediated therapy (that requires MHC I expression on target cells) vs the efficacy of macrophage-mediated therapy.

Though one of the subunits composing MHC I is highly variable among patients, LILRB1 efficiently recognizes a wide range of them, suggesting its relevance even in very heterogeneous patients cohorts.

As MHC is also expressed on normal, healthy cells, specificity and safety must be considered in targeting this signaling as an anti-cancer therapeutic approach. However, treatments with antibodies specifically interfering with the CD47/SIRPalpha interaction are currently in clinical trials showing no toxic effects, while inducing macrophage mediated phagocytosis of leukemic cells (acute myeloid leukemia) and complete disease eradication in pre-clinical models, suggesting the idea that a specific targeting of MHC I/LILRB1 might represent a promising, efficient and safe treatment against cancer cells.

References:

  Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Barkal, Weiskopf, Kao, Gordon, Rosental, Yiu, George, Markovic, Ring, Tsai, McKenna, Ho, Cheng, Chen, Barkal, Ring, Weissman, Maute. Nat Immunol. 2018

  Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. Liu, Wang, Zhao, Tseng, Narayanan, Shura, Willingham, Howard, Prohaska, Volkmer, Chao, Weissman, Majeti. PLoS One. 2015