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Franck Pagès1, Clémence Granier2, Amos Kirilovsky1
1Service d'immunologie biologique, plateforme d'immunomonitoring, hôpital européen Georges-Pompidou, AP-HP, Paris, France; Centre de recherche des Cordeliers, INSERM, eq15, UMRS 1138, Paris, France.
Abstract:
Immunotherapies targeting co-inhibitory receptors recently open a new promising approach of cancer treatment. Indeed, an objective clinical response was observed after treatment by anti-CTLA-4 and anti-PD-1 in many indications but the treatment still failed in 70 to 80 % of cases treated. Given the adverse effects and the high cost of these therapies, there is a need for the development of biomarkers. This review focus on potential predictive biomarkers. In peripheral blood, high level of Il-2 soluble receptor at baseline and absence of ICOS+ CD4-T lymphocytes induction may be associated with the absence of clinical response for melanoma patients treated by ipilimumab (anti-CTLA-4). PD-L1 - PD-1 ligand- expression on cancer lung adenocarcinoma and melanoma is associated with an improved clinical response to anti-PD-1/PD-L1. Nevertheless, a standardization of the biological assays is needed before a clinical translation. CD8-T cell tumor infiltration seems to be a prerequisite to an optimal clinical response after anti-PD-1/PD-L1 administration. In situ high mutational load is associated with a CD8-T cell infiltration and a higher rate of anti-PD-1 and anti-CTLA-4 response. If we consider a more holistic approach, the role of the gut microbiota in the response to these treatments is now well established in pre-clinical experiments. The universal marker is not identified so far, but the reliable marker should be in the tumor compartment and combining multiples markers could be suitable to predict response in different contexts.
Insights
Predictive biomarkers for cancer immunotherapy are crucial as treatments like anti-CTLA-4 and anti-PD-1 fail in most patients. Identifying reliable markers, potentially within tumors or through combined approaches, can improve treatment selection and outcomes.
Area of Science:
- Oncology
- Immunology
- Biomarker Discovery
Background:
- Cancer immunotherapies targeting co-inhibitory receptors (anti-CTLA-4, anti-PD-1) show promise but have limited efficacy in 70-80% of patients.
- High costs and adverse effects necessitate the development of predictive biomarkers to guide treatment decisions.
Purpose of the Study:
- To review and identify potential predictive biomarkers for response to cancer immunotherapies.
- To explore biomarkers in peripheral blood, tumor tissue, and the gut microbiota.
Main Methods:
- Literature review focusing on studies investigating biomarkers associated with clinical response to ipilimumab (anti-CTLA-4) and anti-PD-1/PD-L1 therapies.
- Analysis of biomarkers including soluble interleukin-2 receptor, T-cell populations (ICOS+ CD4-T, CD8-T), PD-L1 expression, tumor mutational load, and gut microbiota composition.
Main Results:
- Peripheral blood markers like high soluble IL-2 receptor and absence of ICOS+ CD4-T induction may predict non-response to anti-CTLA-4 in melanoma.
- PD-L1 expression in lung adenocarcinoma and melanoma correlates with improved response to anti-PD-1/PD-L1, though standardization is needed.
- CD8-T cell tumor infiltration and high in situ mutational load are associated with better responses to both anti-PD-1 and anti-CTLA-4 therapies.
- Gut microbiota composition plays a significant role in immunotherapy response, as shown in preclinical studies.
Conclusions:
- No single universal biomarker has been identified; however, tumor-compartment markers and multi-marker combinations show potential for predicting immunotherapy response.
- Further research and standardization of assays are required for clinical translation of these predictive biomarkers.