Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

Abstract

Purpose: Response rates to immune checkpoint blockade (ICB; anti-PD-1/anti-CTLA-4) correlate with the extent of tumor immune infiltrate, but the mechanisms underlying the recruitment of T cells following therapy are poorly characterized. A greater understanding of these processes may see the development of therapeutic interventions that enhance T-cell recruitment and, consequently, improved patient outcomes. We therefore investigated the chemokines essential for immune cell recruitment and subsequent therapeutic efficacy of these immunotherapies. Experimental Design: The chemokines upregulated by dual PD-1/CTLA-4 blockade were assessed using NanoStringbased analysis with results confirmed at the protein level by flow cytometry and cytometric bead array. Blocking/neutralizing antibodies confirmed the requirement for key chemokines/cytokines and immune effector cells. Results were confirmed in patients treated with immune checkpoint inhibitors using single-cell RNA-sequencing (RNA-seq) and paired survival analyses. Results: The CXCR3 ligands, CXCL9 and CXCL10, were significantly upregulated following dual PD-1/CTLA-4 blockade and both CD8 þ T-cell infiltration and therapeutic efficacy were CXCR3 dependent. In both murine models and patients undergoing immunotherapy, macrophages were the predominant source of CXCL9 and their depletion abrogated CD8 þ T-cell infiltration and the therapeutic efficacy of dual ICB. Single-cell RNA-seq analysis of patient tumor-infiltrating lymphocytes (TIL) revealed that CXCL9/ 10/11 was predominantly expressed by macrophages following ICB and we identified a distinct macrophage signature that was associated with positive responses to ICB. Conclusions: These data underline the fundamental importance of macrophage-derived CXCR3 ligands for the therapeutic efficacy of ICB and highlight the potential of manipulating this axis to enhance patient responses.

Role of Chemokine (C–X–C Motif) Ligand 10 (CXCL10) in Renal Diseases

“…It has been proven that CXCL10 could attenuate the process of new vessel formation and lead to reduced tumor growth in multiple human cancer models, such as non-small-cell lung cancer, colon-rectal cancer [111,112]. In addition, data derived from studies in other human malignancies suggested that this antitumor effect is mainly through the regulation of immune response, currently available evidence indicates that (i) CXCL10 attracts CD8+ and CD4+ effector T cells to tumor sites and sites of inflammation [113], (ii) CXCL10 stimulates immune cells through Th1 polarization and activation [114,115], (iii) CXCL10 are indispensable for robust responses to immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) and improves therapeutic efficacy of radiotherapy [116,117].…”

CD247 Functions as a Prognostic Biomarker for Cutaneous Malignant Melanoma Based on the Analysis of Tumor-immune Microenvironment

“…Then, 908 DEGs (900 upregulation and eight down-regulation) were screened from the immune score and stromal score based on the ESTIMATE algorithm [8]. [18,19]. CXCR3, the receptor for CXCL9 and CXCL10, is highly expressed on CD8 + and CD4 + immune-in ltrating lymphocytes, it is highly likely that local production of CXCL9/10 can modulate T-cell recruitment and activation in human cancers [18][19][20].…”

“…[18,19]. CXCR3, the receptor for CXCL9 and CXCL10, is highly expressed on CD8 + and CD4 + immune-in ltrating lymphocytes, it is highly likely that local production of CXCL9/10 can modulate T-cell recruitment and activation in human cancers [18][19][20]. These chemokines are increased following expose to anti-PD-1 and that they are crucial for therapeutic activity and correlate with patient prognosis [21].…”

Identification of immune-related biomarkers associated with tumorigenesis and prognosis in cutaneous melanoma patients

“…CXCL9, CXCL10 exert their function through binding to C-X-C motif receptor CXCR3 that was highly expressed on the activated T cells [30]. Research shows that CD8 + T cell in ltration is CXCR3 dependent [38]. CD8 + T cell plays important role in tumor microenvironment, which inhibits the proliferation and metastasis of tumor cells.…”