Source: Skin Cancer Foundation/Wikipedia
Source: Skin Cancer Foundation/Wikipedia

A well-aged tumor microenvironment, of the sort found in older cancer patients, may be more susceptible to checkpoint blockade, a form of cancer immunotherapy. This finding, reported by scientists based at the Wistar Institute, suggests that “aging” the tumor microenvironment—by depleting it of immune suppressive T cells—could improve immunotherapy response rates for younger cancer patients.

With each decade of life, the Wistar team discovered, the likelihood of progression of melanoma after treatment with anti-programmed cell death protein 1 (anti-PD1) immunotherapy decreased by 13%. This relationship between patient age and therapeutic response came as a surprise. Prior research by the Wistar team had shown that the tumor microenvironment in older patients promoted melanoma metastasis and resistance to targeted therapy with a BRAF inhibitor.

The new observation, however, seemed solid. It was based on an analysis of a multinational, multi-institutional cohort of almost 500 melanoma patients treated with pembrolizumab, an anti-PD1 receptor checkpoint therapy.

What’s more, the observation was confirmed in mouse models of melanoma. With these models, the Wistar scientists determined that genetically identical tumors responded more to anti-PD1 treatment when transplanted in old mice than in young mice, suggesting that the difference is ascribable to the environment in which the tumor develops.

These results were independent of tumor mutational burden, because both young and aged mice were implanted with genetically identical tumors but had different outcomes.

Further research revealed differences in the immune microenvironment of the two groups of mice. A subpopulation of T cells that are known to be immunosupressive, FOXP3-positive regulatory T cells (Tregs), were fewer in older mice compared with younger mice.

The implications of having T-cell composition shift with age were weighed in a paper prepared by the Wistar team. This paper, “Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations,” appeared June 13 in the journal Clinical Cancer Research.

“We analyzed the relationship between age, response to anti-PD-1, and prior therapy in 538 patients,” wrote the article’s authors. “Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy.”

“Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice.”

Essentially, the researchers analyzed the immune cell composition of the old and young tumor microenvironment both in patient-derived tissues and in mouse models and found a significant decrease in tumor infiltration of Tregs with age. These cells, characterized by expression of the FOXP3 marker, suppress the antitumor immune response and reduce response to anticancer immunotherapy. In parallel with a decrease in the percentage of Tregs, older age correlated with increased presence of killer CD8 T cells, which are the primary effectors in the response to immune checkpoint blockade therapy.

Based on these observations, the researchers depleted Tregs in the young mouse model by targeting them with an antibody against CD25, which is predominantly expressed at high levels on Tregs. Combining anti-PD1 and anti-CD25 treatment was significantly more effective than anti-PD1 alone and they obtained response rates similar to those seen in aged mice, suggesting that overcoming the immune suppression observed in the young microenvironment helps to restore sensitivity to immunotherapy.

“Our study shows that age is an important factor to consider when administering immunotherapy to melanoma patients,” noted Ashani Weeraratna, Ph.D., an associate professor at Wistar and the corresponding author of the paper. “A combination approach to deplete immune suppressive cells in combination with checkpoint blockade therapy might benefit younger patients, although further studies will be required to evaluate more broadly the potential immune toxicities of this approach.”

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