Cancer-cell-secreted CXCL11 promoted CD8+ T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC

Abstract

BackgroundChemotherapy combined with immunotherapy becomes the main trend in lung cancer intervention; however, how chemotherapy promotes the immune function remains elusive. Therefore, we sought to determine how chemotherapy promotes the immune function.MethodsWe determined in 100 NSCLC patients the expression of CD8, functional markers (IFN-γ, Granzyme B, and Perforin) and specific chemokines by quantitative real-time reverse transcriptase-PCR. Functional experiments were carried out to check whether docetaxel (DOC), a chemotherapeutic agent, modifies the expression of HMGB1 and CXCL11, and influences the infiltration properties of CD8+ T cells to the tumor microenvironment. The mechanism of the release of HMGB1 and CXCL11 was determined by flow cytometry, immunofluorescence and western blotting. In in vivo experiment, we confirmed how DOC enhanced the recruitment of HER2-CAR T cells to tumor sites.ResultsWe found that DOC upregulated the expression of chemokine receptor ligand CXCL11 in tumor microenvironment and subsequently enhanced CD8+ T cell recruitment. DOC treatment significantly increased HMGB1 release in an ROS-dependent manner. Recombinant protein HMGB1 stimulated the secretion of CXCL11 via NF-κB activation in vitro. Tumors from DOC-treated mice exhibited higher expression of HMGB1 and CXCL11, more HER2-CAR T cell infiltration, and reduced progression, relative to control. Increased HMGB1 and CXCL11 expressions were positively correlated with prolonged overall survival of lung cancer patients.ConclusionsOur results demonstrate that DOC induces CD8+ T cell recruitment to the tumor microenvironment by enhancing the secretion of HMGB1 and CXCL11, thus improving the anti-tumor efficacy, indicating that modulating the HMGB1-CXCL11 axis might be helpful for NSCLC treatment.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0511-6) contains supplementary material, which is available to authorized users.

Docetaxel Upregulates HMGB1 Levels in Non-small Cell Lung Cancer

“…Changes in the proportion of T cell subsets in peripheral blood during platinumbased combination chemotherapy have been reported in several cancers, including thoracic malignancies, 11) ovarian cancers, 12) pancreatic cancers, 13) and head and neck squamous cell carcinomas. 14) On the other hand, our analysis suggests that numbers of CD4 + and CD8 + T cells during docetaxel monotherapy are not changed significantly. Therefore it is estimated that effects on T cells during chemotherapy vary due to regimens of cytotoxic chemotherapeutics.…”

“…Drug Discovery: Recent Progress and the Future Regular Article 0, 14 (range, days [11][12][13][14][15][16], and 21 (range, days 21-36) and from those treated with EGFR-TKI on days 0, 14 (range, days 13-18), and 28 (range, days 28-52). Peripheral blood mononuclear cells (PBMC) were isolated by gradient density centrifugation using Lymphoprep (Axis Shield, U.K.).…”

PSCA is a target of chimeric antigen receptor T cells in gastric cancer

“…Kheng Newick (2016) noted that blocking protein kinase A (PKA) localization successfully augmented CAR-T cell trafficking and antitumor efficacy [37]. Along the same lines, Qun Gao (2019) found that DOC induced CD8+ T cell recruitment to the tumor microenvironment by enhancing the secretion of HMGB1 and CXCL11 [38], underlining another view that successful trafficking relies on an appropriate match between the chemokine receptors on T cells and the chemokines secreted by the tumors [39]. The evidence reviewed here seems to suggest a combination strategy, including anti-PSCA CAR-T cells and chemical drugs.…”

Persistent anti-NY-ESO-1-specific T cells and expression of differential biomarkers in a patient with metastatic gastric cancer benefiting from combined radioimmunotherapy treatment: a case report

“…44 It has been demonstrated recently that treatment of patients with non-small cell lung cancer with docetaxel, an immune modulating drug, was able to induce CD8 + T cell recruitment to the TME by enhancing the secretion of CXCL-11 and improving the antitumor efficacy. 45 In addition, CXCL-11 was also involved in eliciting a systemic immune response in these patients. 45 Indeed, increased expression of CXCL-11 was positively correlated with prolonged overall survival of the patients.…”

“…45 In addition, CXCL-11 was also involved in eliciting a systemic immune response in these patients. 45 Indeed, increased expression of CXCL-11 was positively correlated with prolonged overall survival of the patients. 45 Other study showed that CXCL-11 modulates the immune-suppressive TME to an immune-supportive one and elucidates a potent and sustained systemic antitumor CD8 + T cell response with enhanced therapeutic efficacy and a survival benefit.…”