Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy

Chow, Melvyn T.; Ozga, Aleksandra J.; Servis, Rachel L.; Frederick, Dennie T.; Lo, Jennifer A.; Fisher, David E.; Freeman, Gordon J.; Boland, Genevieve M.; Luster, Andrew D.

doi:10.1016/j.immuni.2019.04.010

Cited by 467 publications

(463 citation statements)

References 57 publications

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“…Moreover, our data do not discount the importance of CXCL9/10 from other cell types including CD103 þ DCs, which has previously been reported in the context of adoptive cellular therapy and immune checkpoint blockade (12,69). The production of CXCL9/10 by these cells can enhance T-cell priming by facilitating DC:T-cell interactions and result in enhanced antitumor immunity.…”

Section: Discussioncontrasting

confidence: 76%

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

House

Savas

Lai

et al. 2020

Clinical Cancer Research

422

320

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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.

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Section: Discussioncontrasting

confidence: 76%

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

House

Savas

Lai

et al. 2020

Clinical Cancer Research

422

320

View full text Add to dashboard Cite

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“…Decreased serum levels of IL-8 at 2 to 4 weeks after the start of ICI treatment were associated with the response in patients even with the initial pseudoprogression [99]. Induction of CXCR3 ligands in murine melanoma model was described to increase the response to the therapy with anti-PD1 antibodies, and elevated CXCR3 levels were observed in plasma of responding melanoma patients [100].…”

Section: Predicting the Response To The Ici Therapymentioning

confidence: 99%

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

Petrova

Arkhypov

Weber

et al. 2020

IJMS

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Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed.

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“…Importantly, anti-PD-1 efficacy depends on CXCR3 activity, which is a receptor for CXCL9, CXCL10, and CXCL11 chemokines. These CXCR3 ligands are identified as positive predictive biomarkers and their induction in non-responsive mouse tumors could restore the sensitivity to anti-PD-1 (Chow et al, 2019).…”

Section: Tumor Microenvironment Biomarkersmentioning

confidence: 99%

Immuno-Oncology Biomarkers for Personalized Immunotherapy in Breast Cancer

Vafaizadeh

Barekati

2020

Front. Cell Dev. Biol.

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The immune checkpoint blockade therapy has drastically advanced treatment of different types of cancer over the past few years. Female breast cancer is the second leading cause of death in the overall burden of cancers worldwide that is encouraging healthcare professionals to improve cancer care management. The checkpoint blockade therapies combined with novel agents become the recent focus of various clinical trials in breast cancer. However, identification of the patients who are responsive to these therapeutic strategies remained as a major issue for enhancing the efficacy of these treatments. This highlights the unmet need in discovery and development of novel biomarkers to add predictive values for prosperous personalized medicine. In this review we summarize the advances done in the era of biomarker studies and highlight their link in supporting breast cancer immunotherapy.

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Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy

Cited by 467 publications

References 57 publications

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

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

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

Immuno-Oncology Biomarkers for Personalized Immunotherapy in Breast Cancer

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