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Researchers Develop Model for Intra-Tumor

Heterogeneity
Models point towards negative influence of ITH on immune surveillance

by Haylen Caddle, March 19, 2023

Credit: Design Cells/Shutterstock

An international group of researchers has proposed a mathematical model to simulate the

immune system’s response to cancerous tumors. The focus of this model is to simulate and
observe the potential influence of intra-tumor heterogeneity on immune surveillance.

Experimental research has previously indicated that ITH has a strong influence on the
efficiency of the immune system’s defense against tumors. This makes the development of a
model taking into account the effects of ITH highly valuable for furthering research on
tumors and immunotherapy.

Several mathematical models have been developed in the past, but the developers of this
new model argue that theirs is the first to take into account both ITH and the spatial
dynamics of the interactions between tumor and cancer cells.

This group of researchers includes Emma Leschiera, , Luis Almeida, and Chloe Audebert of
the Sorbonne Université in Paris, France, Tommaso Lorenzi of the Politecnico di Torino in
Torino, Italy, and Shensi Shen of Sichuan University in Chengdu, China.

Intra-Tumor Heterogeneity

Through immune surveillance, immune cells in the bloodstream labeled T cells detect and
destroy tumorous cells. This is possible through the production of antigens, molecules that
indicate that a cell is harmful, by the tumor cells which are recognized by the T cells.

“Intra-Tumor Heterogeneity,” or "ITH" for short, refers to the development of distinct sub-
populations of cells in a tumor. As tumors grow and mutate, cells begin to produce
neoantigens that differ from the antigen originally produced by all tumor cells. As these
neoantigens, labeled as sub-clonal antigens, differ from the original clonal antigens they are
not received in the same way by the T cells, thus influencing influencing the process of
immune surveillance.

Developing a Model

The model developed by this group simulates the number of cells remaining in a tumor after
a period of cell surveillance. This number of remaining cells indicates how efficient the
simulated immune system was in destroying the tumor as a more effective immune
surveillance would eliminate a greater number of tumorous cells, leaving a fewer number
remaining than a less effective surveillance would.

The model simulates ITH on two levels: the number of distinct tumor sub-populations and
the percentage of tumor cells producing sub-clonal antigens. These two factors can be
adjusted and the resulting effectiveness of the immune surveillance can be

Their results showed that, with a greater number of populations in the tumor, more tumor
cells remained after cell surveillance, meaning that the simulated immune system was less
effective. The study also found a similar result with the percentage of cells producing sub-
clonal antigens. Like with the number of tumor populations, a greater number of tumor cells
avoided cell surveillance when a greater percentage cells produced sub-clonal antigens.
Together, these two results suggest that higher levels of ITH hinder the effectiveness of
immune surveillance.

The researchers believed the reason for this to be that, with more sub-populations and sub-
clonal antigens, the clonal antigens that the T cells most effectively detect were less
concentrated throughout the tumor. This decreased concentration hindered the ability of
the T cells to pinpoint the location of the tumor, allowing more tumor cells to avoid cell
surveillance.