Posted: March 10, 2016

Tumor Heterogeneity Influences the Immune System's Ability to Fight Cancer

Amy E Blum, M.A.

T Cell of the Immune System.

Every cell in the body displays bits of its contents to the immune system, which searches for signs of external invaders. If the cell displays something abnormal, like a peptide made from an oncogene, this signal alerts the immune system to danger. Bolstering the immune system’s response to these signals is the basis of immunotherapy for cancer.

A new study led by Charles Swanton of the Francis Crick Institute in the United Kingdom found that activation of the immune system against cancer depends on the number and variety of mutations in the tumor. The findings, published on March 3,2016, in Science, provide insight into immune surveillance and suggest that variation, or heterogeneity, within a tumor may be an important predictor of whether patients could benefit from immunotherapy.  

Activating the Immune System

Previous research has shown that tumors display particular mutations as antigens – molecules capable of inducing an immune response – on their cell surface for detection by the immune system. Swanton and his colleagues analyzed the number of antigens, and variety of antigens produced, in 150 cases of lung adenocarcinoma from The Cancer Genome Atlas (TCGA). Strikingly, the number of antigens, also a measure of the number of mutations, correlated positively with increased patient survival. This may appear counterintuitive because mutations cause cancer; however, mutations also present themselves as antigens to the immune system, and attack by the immune system weakens tumors.

The research team also found that the trend between the number of antigens and survival was strongest for tumors that displayed the same antigens across the whole tumor, as opposed to a variety of different antigens in select areas of the tumor. This is because intratumor heterogeneity, variation within a tumor, prevents the immune system from launching an effective attack.

Putting up a Roadblock

If you imagine growth of a homogenous tumor as a getaway car speeding along a superhighway, since a homogenous cancer utilizes only one highway, its dependence on a single route makes it easy for the patrolling immune system to set up checkpoints.  When immune system highway patrol recognizes speeding along this highway and closes it off, the tumor is likely to abate. However, tumors with intratumor heterogeneity do not display antigens uniformly, meaning that they have the choice of many possible roads. The number of possible routes can be too many for the immune system to effectively monitor, and simply alerting the immune system to the presence of the cancer does not increase its ability to close off every road. 

The researchers tested this hypothesis through several experiments and demonstrated that immunotherapy, which helps the immune system recognize cancer cells, is likely more effective for homogenous tumors that express many antigens uniformly.

The team used TCGA data to evaluate the expression of genes involved in activating an immune response as well as genes involved in evading the immune response. They found that tumors that display a large number of antigens uniformly activated a more robust immune response than those that display fewer antigens more heterogeneously. However, the homogenous tumors also expressed higher levels of genes that help the tumor evade the immune system. This makes sense because since the tumor is only taking one road and needs to pass by an alert immune highway patrol, the tumor must compensate by increasing its efforts to avoid detection.

Targeting Immune Evasion

Swanton and his colleagues took their analysis a step further, noting that immunotherapeutic drugs that target immune evasion techniques may work especially well for patients with homogenous tumors that express a large number of antigens.

The researchers analyzed data from a study in which patients were treated with pembrolizumab. This drug targets PD-1, which is a signal that tumors can display in order to become less visible to the immune system. The analysis confirmed that patients with more antigens expressed uniformly were much more likely to benefit from treatment. Sixteen out of eighteen of the patients with high-antigen homogenous tumors had a durable clinical benefit from pembrolizumab, while only two out of eighteen patients with low-antigen heterogeneous tumors benefitted.

These results highlight an important discovery of recent genomic research, that a single tumor is not always a single disease. Heterogeneous tumors can act more like an ecosystem of several smaller tumors, making them more difficult to treat and more prone to drug resistance and relapse. Swanton and his colleagues found that patients with homogenous tumors that display many antigens are more likely to respond robustly to a single immunotherapy than patients with a heterogeneous tumor, who are unlikely to benefit from this type of treatment. These patients may need multiple therapies targeted to specific subpopulations within their tumor. This suggests that measuring and monitoring tumor heterogeneity throughout treatment may help clinicians better predict clinical outcomes and make more informed therapeutic recommendations.  

McGranahan, N., Furness, A.J.S., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S.K., Jamal-Hanjani, M., Wilson, G.A., Birkbak, N.J. Hiley, C.T. et al. (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. DOI: 10.1126/science.aaf1490