Researchers at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Tisch Cancer Center have identified a potential strategy to overcome resistance to immunotherapy in colorectal cancer (CRC) by restoring coordinated interactions between T cells and macrophages within the tumor microenvironment. The findings, published in Cell Reports Medicine, suggest that durable responses to immune checkpoint blockade (ICB) depend not only on activating T cells, but also on reestablishing communication between immune cell populations that work together to eliminate tumors. The study showed that a combination strategy targeting TREM2, LAG3, CTLA4, and PD-1 achieved up to 100% tumor clearance in mismatch repair-deficient colorectal cancer models and more than 70% clearance in mismatch repair-proficient tumors, which are typically resistant to immunotherapy.
“Our findings show that it’s not enough to simply activate the immune system,” said co-senior author Nina Bhardwaj, MD, PhD, director of immunotherapy and professor of medicine at the Icahn School of Medicine. “You also need to restore the communication between immune cells so they can work together effectively against the tumor.”
Currently, anti-PD-1 therapies improve outcomes in some patients with mismatch repair-deficient tumors, but about half of patients with advanced mismatch repair-deficient CRC and most mismatch repair-proficient colorectal cancers fail to respond. In this study, researchers searched for ways to define the immune resistance pathways that limit responses and determine which pathways would need to be targeted simultaneously to overcome immune escape and generate immune memory.
To understand the mechanisms of resistance, the team used orthotopic and patient-derived colorectal cancer models along with murine tumor models and human mismatch repair-deficient colorectal cancer spheroid cultures. The study employed single-cell transcriptomics, spatial analyses, spectral flow cytometry, machine learning, and imaging approaches to characterize immune cell populations and their interactions within tumors.
The analysis of the data identified distinct immune signatures associated with treatment response and resistance. Tumor control during anti-PD-1 therapy was associated with colocalization of MHC-positive, C1Q-positive, CXCL9-positive macrophages and TCF-positive, PRF1-positive T cells. By contrast, resistant tumors contained exhausted T cells expressing TIM3, LAG3, TIGIT, and PD-1, as well as TREM2-positive macrophages concentrated in regions that excluded T cells.
The findings provides a new understanding of effective immunotherapy responses by showing that robust checkpoint blockade activity requires coordinated interactions among multiple immune cell types and not just activation of T cells alone. Specifically, it showed that macrophage remodeling and communication between macrophages and T cells are central components of successful anti-tumor immunity.
In lab studies, the team tested several therapeutic targets individually and in combination, including PD-1, TIM3, TIGIT, LAG3, CTLA4, TREM2, and IFITM. Single-agent targeting of TIM3, TIGIT, LAG3, TREM2, or PD-1 limited tumor growth in mismatch repair-deficient colorectal cancer models, but responses improved when therapies were combined.
The most effective treatment combined blockade of PD-1, LAG3, CTLA4, and TREM2. This approach increased complete tumor elimination rates to as high as 100 percent in mismatch repair-deficient colorectal cancer models and up to 73 percent in mismatch repair-proficient models. Anti-PD-1 monotherapy achieved no complete tumor responses in the models studied.
“This study highlights that overcoming immunotherapy resistance requires more than targeting a single pathway,” said co-senior author Robert M. Samstein, MD, PhD, associate professor of radiation oncology, and immunology and immunotherapy, at the Icahn School of Medicine. “By addressing both T cell dysfunction and the suppressive tumor environment, we can begin to design more effective combination strategies that have the potential to benefit a much broader group of patients.”
The findings build on prior evidence suggesting that T cell exhaustion and suppressive myeloid cells contribute to immune resistance. Earlier research had linked TCF-positive T cells to anti-PD-1 responses in melanoma and associated IL1B-positive monocytes and TREM2-positive macrophages with resistance in CRC and other tumor models.
Importantly, the study found that in mouse models where the initial tumors had been completely eliminated after checkpoint-targeted therapy were also protected against a second tumor inoculation, indicating that the combined approach generated sustained anti-tumor immunity that could reduce recurrence risk.
“This approach effectively reprograms the tumor microenvironment,” said first author Guillaume Mestrallet, PhD, a postdoctoral researcher at Mount Sinai. “By simultaneously reinvigorating T cells and targeting suppressive macrophages, we were able to restore immune coordination and generate powerful anti-tumor responses.”
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