Immune System Holds Clues to Radiotherapy Resistance

The Spina Lab

We want to better understand how tumor irradiation influences our immune response to cancer and whether that understanding can improve existing cancer treatments or even lend itself to develop new ones. 

The Research

“Single-Cell Technologies with Advanced Machine Learning and Gene Network-Based Predictive Algorithms to Identify Novel Targets Driving Radiation Therapy Resistance,” winning project awarded a Life Science Accelerator Award from the HICCC. 

The cancer problem we are solving

More than half of all cancer patients are treated with radiotherapy as part of their cancer-directed therapy. We generally offer cancer patients radiotherapy with a curative or palliative intent: to rid a patient of their cancer or treat cancer pain and progressive disease that could limit quality of life when a cure cannot be achieved. Even when we do treat patients definitively, a cured is not always achieved suggesting varying degrees of radioresistance. Which patients respond less well to radiation therapy and the cause of this heterogenous response is totally not clear. 

We’re approaching this problem from the perspective of the immune system. We know that the immune system is critically important for cancer control. Now, we are actually learning that radiation is a pretty powerful immune modulator, meaning radiation makes changes to the landscape of the immune system within the irradiated tumor and in patient’s blood circulating throughout the body. We want to know if the changes we see in the immune system caused by tumor irradiation are contributing to resistance to radiotherapy in some patients?

What we’ve uncovered so far

For a long time, there was a great deal of interest in how radiation promotes an adaptive anti-tumor immune response—driving the immune system to help treat the tumor. Researchers zoomed in on investigating the T cells, the major effector cells that fight cancer. But if you only look at one cellular compartment, you may miss important changes to another. Perhaps you’ve missed the forest for the trees? 

We now have tools at our fingertips that allow us to profile the immune system –the adaptive and innate immune systems—all at the same time. In other words, by taking a step back and zooming out, we’ve identified that the myeloid cells are just as critically important in the immune system’s response to cancer. We are learning that radiation induces myeloid cells in the tumor, and a subset of those myeloid cells are suppressive. The suppressive myeloid cells blunt the desired anti-tumor adaptive immune response that contribute to cancer control. Now, why does that matter? If you have T cells in the tumor, but then you're increasing the abundance of suppressive cells, effector capacity of the T cells aimed at controlling cancer will be abrogated, or minimized. Said another way, the T cells will be suppressed in their role of spotting and destroying cancer cells. We don't want those suppressive myeloid cells in the tumor.

We've been studying myeloid cells at a basic level before and after tumor irradiation and figuring out how they influence tumor growth. We’re also learning that this is extremely complex. It depends on what you’re observing and when. Time is a key factor in understanding how our immune system is involved in resisting radiation therapy. We conducted experiments in mice, using a small animal radiation research platform (SARRP), looking across the immune compartment at different time points and across [radiation] dose. We’ve discovered that myeloid cells are enriched in the tumors following radiation and may indeed contribute to therapy resistance. 

Our approach

We’re combining single-cell RNA sequencing data generated from tumor samples with advanced algorithms developed by our collaborators in Andrea Califano’s lab to help us carefully understand and identify expression of genes in each individual immune cell, including the suppressive myeloid cells, in the tumor immune environment after irradiation. The computational methods have allowed us to create gene networks at the cellular level and learn how subsets of immune cells behave similarly. With these gene networks, we’re able to also learn about the predicted function of each of these individual cells and that has enabled us to identify novel subpopulations of myeloid cells that are induced within the tumor following radiation and contribute to a suppressive tumor microenvironment.

Next steps

We want to test a variety of molecules to see if they can inhibit these particular suppressive myeloid cells. If we can drug these deleterious cells, the ultimate experiment will be to combine that drug with radiation to see if we can mitigate, or prevent, the induction of these myeloid cells in the tumor. By targeting these suppressive myeloid cells induced by radiation, we may eliminate their ability to dampen the immune response against the tumor, improve response to radiotherapy and overcome immune-mediated radioresistance. 

Our goal with this research

There are no FDA-approved therapies indicated for combination with radiotherapy to overcome radioresistance, other than cytotoxic chemotherapy. We hope to identify a drug that could be combined with radiation to make all tumors respond better to radiation and improve patient outcomes.