1469P - The role of the CXCL12/CXCR4 pathway in the immunotherapy of non-small cell lung cancer

Background

Peripheral blood mononuclear cells (PBMCs) trafficking is regulated by chemokines, which may interfere with their migration towards tumors and even collaborate in the efficacy of immunotherapy. In our study, we investigated whether the CXCL12/CXCR4 pathway plays a role in the efficacy of immunotherapy in non-small cell lung cancer (NSCLC) by analyzing the immunophenotypic profile of PBMCs expressing CXCR4 in peripheral blood (PB) and the expression of its ligand CXCL12 in tumor.

Methods

We identified T, B and NK lymphocytes, monocytes, and dendritic cells expressing CXCR4 in PB using flow cytometry in a prospective cohort of NSCLC patients (experimental group) before starting monotherapy with anti-PD-1 immunotherapy. As a control, we studied patients with advanced cancer before starting any non-immunotherapy treatment. The relative frequency of immune subpopulations in PB was correlated with treatment outcomes. Patients were classified according to high (≥ 55th percentile) or low (≤ 45th percentile) expression in PB for each cellular subpopulation. Uni- and multivariate survival analyses were performed using Cox regression and logistic regression. The expression of CXCL12 in tumor tissue was studied and correlated with the expression of its receptor (CXCR4) in PBMCs.

Results

Experimental group included 39 patients and control group 40. Low expression in PB of CXCR4-expressing CD8+ T lymphocytes was correlated with a greater benefit from immunotherapy: median OS NR vs 22.0 months, HR 0.6, p<0.01, with significance in multivariate models; and median PFS 14.2 vs 5.0 months, HR 0.38, p=0.05, with significance in multivariate models. ORR: trend towards significance. These differences were specific to the experimental group and were not observed in the controls. Low expression in PB of these lymphocytes was correlated with a higher expression of CXCL12 in tumors (trend towards significance: p=0.14). No significant results were obtained in any of the other subpopulations studied.

Conclusions

Patients diagnosed with advanced NSCLC with low expression of cytotoxic T lymphocytes in PB expressing CXCR4 show greater benefit from immunotherapy, due to greater tumor infiltration of lymphocytes receiving homing signals from the expression of CXCL12 in the tumor.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Institulo de Investigación Sanitaria Princesa.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.