ICML 2021 | Immune suppression and dysfunction in lymphoma tumors

In lymphomas, I think what we have come to realize over the last number of years is that it’s not just about the malignant B-cell. So I think our initial studies were really trying to understand the genetics of the malignant B-cell and factors that would promote its growth and survival. But I think we’ve come to realize over time that many other immune cells interacts with the malignant B-cell and promote or try and restrict its growth.

We’ve come to realize that although there are T-cells that are able to target the malignant cell, they’re not able to really eradicate the malignant cell. And over time their function becomes increasingly suppressed and the tumor begins to progress.

So our understand the ending of what really is dysfunctional or suppressed about that T-cell is critical to moving the field forward, particularly if we’re going to work more in the areas of immunotherapy. So what we found focused on in that discussion and presentation was the fact that really there are multiple barriers to an effective immune response, but two particularly that we were discussing. The first is immune suppression and part of that is because T-cells are regulated by other cells in their environment and normal biology requires that if a T-cell becomes activated, there’s actually mechanisms in place to switch it off over time.

And tumors really co-opt those mechanisms and promote an environment that really keeps suppressing the anti-tumor immune response and cells like T regulatory cells, monocytes and macrophages and myeloid derived suppressor cells, are typically the types of cells that will dampen an immune response. So, as we think about how to use that in the future inhibiting the inhibitors is going to be an important strategy to allow those effector cells to do a better the job.

And on the other side is the whole question of dysfunction. So typically if the immune response is continually stimulated over time, those cells become weary as it were in doing good and slowly become increasingly suppressed, dysfunctional and immunologically exhausted. And they put many proteins on their surface, which make them very vulnerable to being switched off by the immune environment. So again, if we really want to have these effector cells remain effective, it’s important to block those inhibitory signals and continue to promote the ability of those cells to remain activated.

So if we put that together and say, how does that matter as far as treatments in the future? Really want to have strategies, that are going to prevent cells from being shot down by their neighbors and keep them activated by preventing them from receiving negative signals, that would shut them down. If we can do that often in combination, even with additional strategies, that will really improve the outcome of patients with lymphoma.