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Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma.

ABSTRACT: Radiofrequency ablation (RFA) of colorectal liver metastases activates a specific T-cell response that is ineffective in avoiding recurrence. Recently, local immunomodulation garnered interests as a way to improve the immune response. We were interested in improving the RFA immune response priming to propose a curative treatment of colorectal cancer (CRC) based on antitumor immunity. First, we demonstrated that the RFA did not increase the tumor infiltrating lymphocytes in secondary distant tumors of patients and in mice model and could not avoid relapse. Remarkably, RFA and in situ immunomodulation with GM-CSF-BCG hydrogel induced complete cure of microscopic secondary lesions in mice, related to a strong specific immune response. Then, we demonstrated that the immune escape of large secondary lesions was reversed by addition of the systemic PD-1 blockade to the in situ immunomodulation. The lack of an effective distant immune response in patients treated with RFA confirmed the relevance of this new combination strategy. Increasing the in situ priming response of radiofrequency ablation provides effective adjuvants to induce an abscopal effect. In the case of large lesions, synergy between PD1 blockade inhibitor, ineffective alone or after single RFA, with in situ immunomodulation, could lead to reconsideration of the use of checkpoint inhibition in metastatic MSS CRC.

SUBMITTER: Lemdani K

PROVIDER: S-EPMC6350685 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma.

Lemdani Katia K Mignet Nathalie N Boudy Vincent V Seguin Johanne J Oujagir Edward E Bawa Olivia O Peschaud Frédérique F Emile Jean-François JF Capron Claude C Malafosse Robert R

Oncoimmunology 20190110 3

Radiofrequency ablation (RFA) of colorectal liver metastases activates a specific T-cell response that is ineffective in avoiding recurrence. Recently, local immunomodulation garnered interests as a way to improve the immune response. We were interested in improving the RFA immune response priming to propose a curative treatment of colorectal cancer (CRC) based on antitumor immunity. First, we demonstrated that the RFA did not increase the tumor infiltrating lymphocytes in secondary distant tumo ...[more]

PMID: 30723580

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Project description:PurposeWhile surgical resection is a cornerstone of cancer treatment, local and distant recurrences continue to adversely affect outcome in a significant proportion of patients. Evidence that an alternative debulking strategy involving radiofrequency ablation (RFA) induces antitumor immunity prompted the current investigation of the efficacy of performing RFA prior to surgical resection (pre-resectional RFA) in a preclinical mouse model.Experimental designTherapeutic efficacy and systemic immune responses were assessed following pre-resectional RFA treatment of murine CT26 colon adenocarcinoma.ResultsTreatment with pre-resectional RFA significantly delayed tumor growth and improved overall survival compared to sham surgery, RFA, or resection alone. Mice in the pre-resectional RFA group that achieved a complete response demonstrated durable antitumor immunity upon tumor re-challenge. Failure to achieve a therapeutic benefit in immunodeficient mice confirmed that tumor control by pre-resectional RFA depends on an intact adaptive immune response rather than changes in physical parameters that make ablated tumors more amenable to a complete surgical excision. RFA causes a marked increase in intratumoral CD8+ T lymphocyte infiltration, thus substantially enhancing the ratio of CD8+ effector T cells: FoxP3+ regulatory T cells. Importantly, pre-resectional RFA significantly increases the number of antigen-specific CD8+ T cells within the tumor microenvironment and tumor-draining lymph node but had no impact on infiltration by myeloid-derived suppressor cells, M1 macrophages or M2 macrophages at tumor sites or in peripheral lymphoid organs (i.e., spleen). Finally, pre-resectional RFA of primary tumors delayed growth of distant tumors through a mechanism that depends on systemic CD8+ T cell-mediated antitumor immunity.ConclusionImproved survival and antitumor systemic immunity elicited by pre-resectional RFA support the translational potential of this neoadjuvant treatment for cancer patients with high-risk of local and systemic recurrence.

Dataset Information

Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma.

Publications

Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma.

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