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Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal
Shogo Takei1,2, Yosuke Tanaka3, Yi-Tzu Lin4
1Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Japan.
Background:
Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations.
Methods:
Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies.
Results:
The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial.
Conclusions:
We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.
Insights
This study identified biomarkers for immune checkpoint inhibitor (ICI) combinations in microsatellite stable colorectal cancer (CRC). Findings reveal distinct molecular features linked to treatment response, aiding future immunotherapy development for MSS/pMMR CRC.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Immune checkpoint inhibitor (ICI) combinations are emerging cancer treatments.
- Efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable.
- Predictive biomarkers for ICI combinations in MSS/pMMR CRC are needed.
Purpose of the Study:
- To perform multiomic characterization of MSS/pMMR CRC tumors.
- To identify predictive biomarkers for patient response to ICI combinations.
- To facilitate the development of novel ICI combinations.
Main Methods:
- Multiomic analysis including whole-exome sequencing, RNA sequencing, and multiplex immunohistochemistry.
- Tumor samples from patients with MSS/pMMR CRC treated with regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) were analyzed.
- Biomarker analysis was conducted on samples from 22 (REGONIVO) and 23 (TASNIVO) patients.
Main Results:
- Upregulation of epithelial-mesenchymal transition and cancer-associated fibroblast pathways in REGONIVO responders.
- Upregulation of G2M checkpoint pathway in TASNIVO responders; MYC pathway in REGONIVO non-responders.
- Consensus molecular subtype 4 associated with response and progression-free survival in REGONIVO trial; POLE mutations associated with response in TASNIVO trial. Increased CD8+ T cells, regulatory T cells, and M2 macrophages in REGONIVO responders.
Conclusions:
- Molecular features, particularly tumor microenvironment factors, are associated with response to REGONIVO and TASNIVO.
- Identified biomarkers can predict treatment efficacy for MSS/pMMR CRC.
- Findings support the development of future immunotherapy combinations for MSS/pMMR CRC.
