Introduction: Are We Meaningfully Impacting the Tumor Microenvironment?

Metastatic colorectal cancer is largely driven by mismatch repair-proficient/microsatellite stable (MSS) tumors, which are characterized by immune exclusion, hypoxia, and a suppressive tumor microenvironment. In refractory disease, this biology reflects an evolutionarily adapted ecosystem that resists therapy, raising the central question of whether current strategies truly reprogram the TME or only transiently modulate it.

Watch Round 1.

Aparna Parikh: Thank you all for joining us today. Today, we're going to be talking about refractory metastatic colorectal cancer, and we'll be debating with my colleagues whether we are meaningfully impacting the tumor microenvironment. My name is Dr Aparna Parikh. I'm an associate professor of medicine at Harvard Medical School and program director of GI Oncology at the Mass General Brigham Cancer Institute.

So today we have several learning objectives. Number one, to characterize refractory metastatic colorectal cancer as a biologically immune-excluded and evolutionarily adaptive tumor state. We'll also be trying to distinguish between transient modulation of the tumor microenvironment and meaningful biologic reprogramming. Finally, we'll go through emerging data using the lens of a tumor ecosystem disruption.

So, to level set, metastatic colorectal cancer is a biologically heterogeneous group of patients. To date, metastatic colorectal cancer can be divided into two groups. The first group, which comprises most patients, is microsatellite stable. This constitutes around 85% of metastatic colorectal cancers. The other group is MSI-high. MSI-high tumors constitute around 15% of all colorectal cancers, a slightly lower percentage in the metastatic setting, but they are characterized by a higher tumor mutational burden and a higher density of CD8+ tumor-infiltrating lymphocytes. These tumors have historically been referred to as hot tumors, given their immune infiltration, which is seen with these tumors. MSS tumors historically have been called cold tumors. These tumors exhibit minimal T-cell infiltration and historically demonstrate lower PD-L1 expression than MSI-high tumors.

So again, as alluded to, for years we have been trying to understand why MSS tumors act as an immune-excluded state and why MSS tumors have not been able to demonstrate activity with immune checkpoint inhibitors. MSS tumors demonstrate immune exclusion, and this immune exclusion is really mediated by several factors. Number one, we see impaired T-cell trafficking. We observe a high proportion of MDSCs, high stromal barriers, and hypoxia-driven signaling.

The tumor microenvironment in these cold tumors has been shown to drive resistance to checkpoint inhibitors. What you see in the TME is aberrant angiogenic and receptor tyrosine kinase signaling. This aberrant signaling of angiogenic factors, as well as RTK signaling, contributes to the abnormal tumor vasculature. This abnormal tumor vasculature results in a hypoxic environment and acidosis within the TME. This persistent hypoxia and metabolic stress continue to promote inflammation, promote myeloid-mediated immune suppression, stromal remodeling, and resistance to therapies, including radiotherapy, chemotherapy, and notably immunotherapy.

Refractory metastatic colorectal cancer patients represent a heavily pretreated disease state. Evolutionarily, it has adapted to a tumor ecosystem shaped by tumor exclusion, immune exclusion, hypoxia, stromal dysregulation, and clonal selection under therapeutic pressure. We know that the TME is largely what actively sustains and shields the tumor from effective suppression. Most of these tumors are MMR proficient, also known as microsatellite-stable tumors.

So, the central question for today's discussion, and I'll be debating this with my colleagues today, is, do current strategies meaningfully disrupt this refractory biological state? Or do these strategies only modulate the immune microenvironment rather than reprogram it? To understand this today, we'll really start to pay close attention to tumor microenvironment interactions, and this understanding will be pivotal for us to inform future therapeutic evolution in the refractory metastatic colorectal cancer space.