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Updated: Jun 13, 2025
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Identification of microenvironment features associated with primary resistance to anti-PD-1/PD-L1 + antiangiogenesis
Sophie Cousin1, Jean-Philippe Guégan2, Kohei Shitara3
1Department of Medicine, Institut Bergonié, 229 cours de l'Argonne, Bordeaux, 33000, France.
Abstract:
Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation.
Insights
Regorafenib plus avelumab showed durable responses in advanced gastric cancer (AGC). However, M2 macrophages and S100A10 overexpression in tumors, along with specific cytokines, were linked to resistance, guiding future therapeutic strategies.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Anti-angiogenic agents and immune checkpoint inhibitors have synergistic potential in advanced gastric cancer (AGC).
- Early studies in Asian patients showed promise for combined VEGF and PD-L1 inhibition.
Purpose of the Study:
- To evaluate the efficacy and resistance mechanisms of regorafenib plus avelumab in Caucasian AGC patients.
- To identify biomarkers associated with response and resistance to this combination therapy.
Main Methods:
- Phase II REGOMUNE study in Caucasian patients with advanced gastric cancer.
- Combination therapy with regorafenib (multi-tyrosine kinase inhibitor) and avelumab (anti-PD-L1 antibody).
- Biomarker profiling of tumor microenvironment and peripheral cytokines in responders and non-responders.
Main Results:
- 19% of patients achieved deep and durable responses, with median duration of response not reached.
- Non-responders showed increased M2 macrophages and S100A10 overexpression in tumors.
- Elevated peripheral cytokines (CSF-1, IL-4, IL-8, TWEAK) correlated with poor outcomes, indicating macrophage infiltration mediates resistance.
Conclusions:
- The combination of regorafenib and avelumab offers durable responses in a subset of AGC patients.
- Tumor M2 macrophage infiltration and S100A10 expression are key resistance mechanisms.
- Peripheral cytokine profiles may predict treatment outcomes and highlight the importance of tumor microenvironment modulation.
