CXCL13 Positive Cells Localization Predict Response to Anti-PD-1/PD-L1 in Pulmonary Non-Small Cell Carcinoma
Fatemeh Vahidian1,2, Fabien C Lamaze1, Cédrik Bouffard1,2
1Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Quebec City, QC G1V 4G5, Canada.
Abstract:
Background: Immune checkpoint inhibitors (ICIs) have revolutionized non-small cell lung cancers (NSCLCs) treatment, but only 20-30% of patients benefit from these treatments. Currently, PD-L1 expression in tumor cells is the only clinically approved predictor of ICI response in lung cancer, but concerns arise due to its low negative and positive predictive value. Recent studies suggest that CXCL13+ T cells in the tumor microenvironment (TME) may be a good predictor of response. We aimed to assess if CXCL13+ cell localization within the TME can predict ICI response in advanced NSCLC patients. Methods: This retrospective study included 65 advanced NSCLC patients treated with Nivolumab/Pembrolizumab at IUCPQ or CHUM and for whom a pretreatment surgical specimen was available. Good responders were defined as having a complete radiologic response at 1 year, and bad responders were defined as showing cancer progression at 1 year. IHC staining for CXCL13 was carried out on a representative slide from a resection specimen, and CXCL13+ cell density was evaluated in tumor (T), invasive margin (IM), non-tumor (NT), and tertiary lymphoid structure (TLS) compartments. Cox models were used to analyze progression-free survival (PFS) and overall survival (OS) probability, while the Mann-Whitney test was used to compare CXCL13+ cell density between responders and non-responders. Results: We showed that CXCL13+ cell density localization within the TME is associated with ICI efficacy. An increased density of CXCL13+ cells across all compartments was associated with a poorer prognostic (OS; HR = 1.22; 95%CI = 1.04-1.42; p = 0.01, PFS; HR = 1.16; p = 0.02), or a better prognostic when colocalized within TLSs (PFS; HR = 0.84, p = 0.03). Conclusion: Our results support the role of CXCL13+ cells in advanced NSCLC patients, with favorable prognosis when localized within TLSs and unfavorable prognosis when present elsewhere. The concomitant proximity of CXCL13+ and CD20+ cells within TLSs may favor antigen presentation to T cells, thus enhancing the effect of PD-1/PD-L1 axis inhibition. Further validation is warranted to confirm the potential relevance of this biomarker in a clinical setting.
Insights
CXCL13+ T cells predict immune checkpoint inhibitor response in non-small cell lung cancer (NSCLC). Their location in tertiary lymphoid structures (TLS) indicates a favorable prognosis, while elsewhere suggests a poor prognosis.
Area of Science:
- Oncology
- Immunology
- Pathology
Background:
- Immune checkpoint inhibitors (ICIs) offer revolutionary treatment for non-small cell lung cancer (NSCLC), yet response rates remain limited to 20-30%.
- PD-L1 expression is the sole approved biomarker for ICI response in NSCLC, but its predictive value is suboptimal.
- CXCL13+ T cells within the tumor microenvironment (TME) are emerging as potential predictors of ICI efficacy.
Purpose of the Study:
- To investigate the predictive value of CXCL13+ cell localization within the tumor microenvironment (TME) for immune checkpoint inhibitor (ICI) response in advanced non-small cell lung cancer (NSCLC).
Main Methods:
- Retrospective analysis of 65 advanced NSCLC patients treated with Nivolumab/Pembrolizumab.
- Immunohistochemistry (IHC) for CXCL13 on tumor specimens to quantify cell density in tumor, invasive margin, non-tumor, and tertiary lymphoid structure (TLS) compartments.
- Cox models and Mann-Whitney tests were used to correlate CXCL13+ cell density with progression-free survival (PFS) and overall survival (OS).
Main Results:
- Increased CXCL13+ cell density in most TME compartments correlated with poorer overall survival (OS) and progression-free survival (PFS).
- Conversely, higher CXCL13+ cell density specifically within tertiary lymphoid structures (TLS) was associated with improved PFS.
- These findings highlight the differential prognostic impact of CXCL13+ cell localization within the tumor microenvironment.
Conclusions:
- CXCL13+ cell localization within the tumor microenvironment (TME) is a significant predictor of immune checkpoint inhibitor (ICI) efficacy in advanced non-small cell lung cancer (NSCLC).
- Favorable prognosis is linked to CXCL13+ cells within tertiary lymphoid structures (TLS), potentially enhancing antigen presentation.
- Unfavorable prognosis is associated with CXCL13+ cells in other TME compartments, suggesting distinct roles and warranting further clinical validation.
