Related Experiment Video
Updated: Jun 17, 2026
Endobronchial Ultrasound-guided Intratumoral Injection of Cisplatin for the Treatment of Isolated Mediastinal Recurrence of Lung Cancer
Published on: February 12, 2017
Spatial predictors of response to chemo-immunotherapy in microsatellite stable metastatic colorectal cancer
Joan Choo1, Joseph J Zhao2, Mai Chan Lau3,4
1Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.
Abstract:
Microsatellite-stable (MSS) colorectal cancers (CRC) are largely unresponsive to immune checkpoint inhibition (ICI). The MAYA trial used temozolomide (TMZ) in MGMT-silenced MSS mCRC, hypothesizing that TMZ-induced hypermutation could sensitize tumors to ICI; the primary endpoint was met, showing durable responses with TMZ plus ipilimumab and nivolumab. We perform integrated spatial, transcriptomic, and immune profiling of longitudinal tumor and blood samples from patients treated on the MAYA trial. Post-TMZ increases in tumor mutational burden associate with improved progression-free survival. Spatial profiling demonstrates that clinical benefit is greatest in permissive tumor microenvironments. Responders exhibit enrichment of cytotoxic T cells across tumor and stromal compartments, whereas non-responders display heterogeneous cellular neighborhoods, with fibroblasts in close spatial proximity to T cells, consistent with barriers to immune-mediated clearance. Longitudinal peripheral immune profiling shows that early upregulation of TIGIT and PD-1 following TMZ exposure predicts resistance. Together, these findings indicate that both mutational evolution and spatial immune architecture contribute to immune sensitization in MGMT-silenced MSS CRC. Clinical Trial Identification: NCT03832621.
Insights
Temozolomide (TMZ) can sensitize microsatellite-stable colorectal cancer (MSS CRC) to immune checkpoint inhibition (ICI) by increasing tumor mutations. This study reveals that tumor microenvironment and T-cell infiltration are key factors for treatment response.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Microsatellite-stable colorectal cancer (MSS CRC) shows limited response to immune checkpoint inhibition (ICI).
- The MAYA trial investigated temozolomide (TMZ) in MGMT-silenced MSS mCRC to induce hypermutation and enhance ICI sensitivity.
- The primary endpoint of the MAYA trial was met, demonstrating durable responses with TMZ combined with ipilimumab and nivolumab.
Purpose of the Study:
- To investigate the mechanisms underlying the response to TMZ plus ICI in MSS CRC.
- To analyze the integrated spatial, transcriptomic, and immune profiles of longitudinal tumor and blood samples from MAYA trial patients.
- To identify biomarkers predicting response or resistance to this combination therapy.
Main Methods:
- Integrated analysis of spatial, transcriptomic, and immune profiling on longitudinal tumor and blood samples.
- Assessment of tumor mutational burden (TMB) changes post-TMZ treatment.
- Spatial profiling to characterize tumor microenvironment (TME) architecture.
- Longitudinal peripheral immune profiling to identify predictive immune markers.
Main Results:
- Increased tumor mutational burden after TMZ treatment correlated with improved progression-free survival.
- Clinical benefit was associated with permissive tumor microenvironments.
- Responders showed increased cytotoxic T cells, while non-responders had fibroblasts hindering immune clearance.
- Early upregulation of TIGIT and PD-1 in peripheral blood after TMZ predicted resistance.
Conclusions:
- Mutational evolution and spatial immune architecture are critical for immune sensitization in MGMT-silenced MSS CRC.
- TMZ can overcome resistance to ICI in MSS CRC by altering the tumor immune microenvironment.
- TIGIT and PD-1 expression in peripheral blood may serve as early biomarkers for predicting resistance to TMZ-based ICI therapy.
