Celebrating the 10th Anniversary
A decade of discoveries in Cancer Discovery. For the community. By the Community.
Their impactful studies. In their words.
Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy
Comments by Lisa Coussens, PhD
That paper demonstrated that if you could relieve myeloid-mediated T-cell suppression, you could invoke a functional T-cell response and slow tumor progression... it's a very important paper.
I've been studying myeloid cells for a very long time, but this was certainly one of the first papers to demonstrate that by relieving or diminishing the myeloid component in a solid tumor, you could relieve T-cell suppression and invoke a very significant T-cell response that could impact tumor development and progression. Obviously the last 10–15 years have really focused on development of the T-cell checkpoint inhibitors and understanding how they play a role in regulating T-cell biology and their impact on cancer medicine. But the paper recognized that T cells don't necessarily do their job in tumors because they're suppressed by many mechanisms from a diversity of myeloid cells. That paper demonstrated that if you could relieve myeloid-mediated T-cell suppression, you could invoke a functional T-cell response and slow tumor progression. So in that regard, it's a very important paper. And in the last 10 years, there's clearly been a transformation where now even classical T-cell immunologists think about the myeloid compartment in that the myeloid compartment impacts what a T cell can do. Going forward into the clinic for the patients that don't respond to the currently approved T-cell checkpoint inhibitors, combining them with various types of myeloid antagonists is certainly going to be part of standard of care in the not-too-distant future.
Comments by David DeNardo, PhD
...what I think was important about the findings was that while many investigators at the time were targeting the T cells—and clearly in some settings this is enough—the concept of targeting the innate immune components or depleting them to impact how well a T cell works in response to chemotherapy was not around at that time.
We’d been trying to understand how chronic inflammatory scenarios during the development of cancer might differentially sculpt the immune response to not favor T cell–mediated immune surveillance. We came to realize that many of these chronic inflammatory responses also involved wound healing, and there are cellular players in that process that include macrophages. Macrophages might play a deleterious role in cancer development and in the T-cell response, and in particular they might play a deleterious role when wounding is engaged by therapeutics such as chemotherapy, which we studied. Thinking about it now, what I think was important about the findings was that while many investigators at the time were targeting the T cells—and clearly in some settings this is enough—the concept of targeting the innate immune components or depleting them to impact how well a T cell works in response to chemotherapy was not around at that time—it’s more favored now. We could have predicted that a chronic inflammatory wound-healing mediator would stop T cells, but it was a matter of showing this could occur or would occur in animal models, and then we combined it with human data, which I think was the compelling part. The study highlighted that you could come at cancer from more than one angle and there are going to be a subset of cancers that you could improve with a combination of chemotherapy and immunotherapy but not a T cell–directed immunotherapy. That concept still exists and is still exciting, and in my lab (I was a postdoc at the time of the paper) we still work on similar concepts: what are the mediators of wound healing that might be a barrier to therapy, and can we mitigate these in different ways?