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Published on: March 14, 2019
Baseline Tumor Features and Systemic Immune Dynamics Underlying Efficacy in MSS Metastatic Colorectal Cancer Treated
Jian Ye1, Chongkai Wang1, Colt A Egelston2
1Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California.
Abstract:
Microsatellite-stable metastatic colorectal cancer (MSS mCRC) remains resistant to conventional immunotherapies. In a phase I trial, we observed encouraging efficacy of the combination of regorafenib, ipilimumab, and nivolumab (RIN), with a 27.6% overall response rate and a median overall survival of 20 months. The most pronounced benefits were observed in patients without liver metastases. To uncover immunologic mechanisms underlying response and resistance, we performed correlative studies of the tumor microenvironment (TME) and systemic immune features. Tumor biopsies from 8 patients and peripheral blood samples from 29 patients with MSS mCRC were collected and analyzed at baseline and during treatment. At baseline, tumors from good responders exhibited enhanced proliferation, DNA repair pathways, and STING expression, whereas poor responders showed enrichment of complement and metabolism pathways. In peripheral blood, good responders had a higher CD4/CD8 T-cell ratio, increased dendritic cells, and intact type 1 cytokine responses. In contrast, poor responders exhibited more effector T-cell differentiation, elevated immune checkpoint molecule expression, and increased DNA damage in lymphocytes. In good responders, RIN therapy increased tumor-infiltrating lymphocytes and upregulated immune activation genes, accompanied by heightened T-cell proliferation and activation in peripheral blood, including the expansion of low-frequency T-cell receptor clones in CD8+ T cells. Patients with liver metastases exhibited T-cell senescence and metabolic hyperactivation, correlating with therapeutic resistance. These findings highlight that preexisting tumor immunogenicity and T-cell functional capacity are associated with response to RIN therapy and that RIN treatment may facilitate both systemic T-cell activation and local TME modulation.
Insights
Regorafenib, ipilimumab, and nivolumab (RIN) show promise for microsatellite-stable metastatic colorectal cancer (MSS mCRC). Pre-existing tumor immunity and T cell function predict response to this immunotherapy combination.
Area of Science:
- Oncology
- Immunotherapy
- Colorectal Cancer Research
Background:
- Microsatellite-stable metastatic colorectal cancer (MSS mCRC) exhibits resistance to conventional immunotherapies.
- The combination of regorafenib, ipilimumab, and nivolumab (RIN) demonstrated encouraging efficacy in a phase I trial.
Purpose of the Study:
- To investigate the immunological mechanisms behind response and resistance to RIN therapy in MSS mCRC.
- To correlate tumor microenvironment (TME) and systemic immune features with treatment outcomes.
Main Methods:
- Correlative analysis of tumor biopsies and peripheral blood from MSS mCRC patients (n=8 and n=29, respectively) at baseline and during RIN treatment.
- Assessment of TME features, including proliferation, DNA repair, STING, complement, and metabolism pathways.
- Analysis of peripheral blood immune cell populations (T cells, dendritic cells), cytokine responses, and immune checkpoint molecule expression.
Main Results:
- Good responders showed enhanced baseline tumor proliferation, DNA repair, STING expression, higher CD4/CD8 T cell ratio, increased dendritic cells, and intact type 1 cytokine responses.
- Poor responders exhibited enriched metabolism pathways, effector T cell differentiation, elevated immune checkpoints, and lymphocyte DNA damage.
- RIN therapy increased tumor-infiltrating lymphocytes and immune activation genes in good responders, with enhanced peripheral T cell proliferation and activation.
- Patients with liver metastases displayed T cell senescence and metabolic hyperactivation, correlating with resistance.
Conclusions:
- Pre-existing tumor immunogenicity and T cell functional capacity are associated with response to RIN therapy in MSS mCRC.
- RIN treatment may enhance systemic T cell activation and modulate the local TME.
- Liver metastases represent a challenge, associated with T cell senescence and resistance to RIN therapy.
