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

“A Functional CD8 T Cell Response after PD-1 Blockade Is Dependent on CXCR3 Given the reported role of CXCR3 in T cell recruitment into tumors and the importance of pre-existing intratumoral CD8 T cells for effective PD-1 blockade therapy (Tumeh et al., 2014), we hypothesized that the reduced therapeutic effect of anti…”

“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”

“Correlative human studies have highlighted the potential importance of chemokines for T cell infiltration into tumors and for patient survival (Bindea et al., 2013; Messina et al., 2012).”

“To this end, we used fingolimod (FTY720) (a functional antagonist of the S1P1 receptor) to block the egress of T cells from the lymphoid organs (Matloubian et al., 2004) one day before the initiation of anti-PD-1 therapy (Figure 2A).”

“Although CD8 T cells are considered the primary target of anti-PD-1, anti-PD-1 can directly affect macrophages as well (Gordon et al., 2017).”

“CXCR3 on CD8 T Cells Is Essential for Anti-PD-1Mediated CD8 T Cell Activation CXCR3 is expressed not only on T cells but also on other hematopoietic cells, such as innate lymphocytes and plasmacytoid DCs (Griffith et al., 2014).”

“Previous studies demonstrated that terminally exhausted CD8+ T cells upregulate their expression of granzyme B (Im et al., 2016; Utzschneider et al., 2016).”

“In the tumor microenvironment, PD-L1 is upregulated on antigen-presenting cells and/or tumors cells, and its binding to PD-1 on CD8 T cells dampens their cytokine production, proliferation, and migration (Sharpe and Pauken, 2018).”

“It has been suggested that the efficacy of immune checkpoint blockade relies on T cells already present in tumors, given that FTY720 administration before treatment did not affect the efficacy of immunotherapy (Garris et al., 2018; Siddiqui et al., 2019; Spranger et al., 2014; Wang et al., 2016).”

“The extent of enhancement of the CD8 T cell response by PD-1 blockade is one of the critical determinants of the efficacy of anti-PD-1 therapy (Huang et al., 2017).”

“The CXCR3 chemokine system plays an important role in CD8 T cell recruitment into tumors in adoptive transfer models (Mikucki et al., 2015; Spranger et al., 2017).”

“CD103+ DCs excel in the priming and cross-presentation of cell-associated antigens to CD8+ T cells and are critical for the efficacy of anti-PD-1 cancer therapy (Salmon et al., 2016; Sánchez-Paulete et al., 2016).”

“We further investigated whether the T cell response against Adpgk, a well-described neoantigen expressed in MC38 tumors (Yadav et al., 2014), was affected inCxcr3 / mice.”

“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”

“CXCR3 and its ligands guide the recruitment of effector T cells into the inflamed peripheral tissue in type 1 inflammatory responses (Dufour et al., 2002; Hancock et al., 2001; Hancock et al., 2000; Harris et al., 2012; Khan et al., 2000; Rashighi et al., 2014).”

“The CXCR3 chemokine system is also relevant in the therapeutic efficacy of chemotherapy (Sistigu et al., 2014).”

“CXCR3, a chemokine receptor for the interferon-inducible chemokines CXCL9, CXCL10, and CXCL11, is highly expressed on activated T cells and plays essential roles in the spatial distribution, migratory behavior, and function of T cells (Groom and Luster, 2011a; Groom and Luster, 2011b).”

“It has been suggested that the efficacy of immune checkpoint blockade relies on T cells already present in tumors, given that FTY720 administration before treatment did not affect the efficacy of immunotherapy (Garris et al., 2018; Siddiqui et al., 2019; Spranger et al., 2014; Wang et al., 2016).”

“In contrast, another study found that a systemic immune response is required for effective checkpoint blockade therapy (Spitzer et al., 2017).”

“PD-L1 on tumor cells can directly inhibit the cytotoxic function of CD8+ T cells, and blockade of the PD-1-PD-L1 interaction enhances the direct CD8+ T cell killing of tumor cells (Juneja et al., 2017).”

“CD8 T cells play a vital role in tumor eradication through the production of cytotoxic molecules, such as perforin and granzyme, and cytokines, such as interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a) (Martı́nez-Lostao et al., 2015).”

“In particular, immune checkpoints, such as the programmed cell death-1 (PD-1) and programmed death ligand-1 (PD-L1) pathway (PD-1-PD-L1), have been exploited by tumors as a critical immunosuppressive mechanism to evade T cell immunity (Hashimoto et al., 2018).”

“CXCR3 and its ligands guide the recruitment of effector T cells into the inflamed peripheral tissue in type 1 inflammatory responses (Dufour et al., 2002; Hancock et al., 2001; Hancock et al., 2000; Harris et al., 2012; Khan et al., 2000; Rashighi et al., 2014).”

“However, it is well established that the microenvironment of tumors is frequently immunosuppressive, rendering CD8+ T cells dysfunctional and promoting tumor progression (Speiser et al., 2016).”

“There is rapid proliferation of CD8+ T cells within tumors after PD-1 blockade (Spranger et al., 2014; Wei et al., 2017), suggesting that the pre-existing tumor-infiltrating CD8+ T cell population is sufficient for eliciting a therapeutic response.”

“CXCR3 and its ligands guide the recruitment of effector T cells into the inflamed peripheral tissue in type 1 inflammatory responses (Dufour et al., 2002; Hancock et al., 2001; Hancock et al., 2000; Harris et al., 2012; Khan et al., 2000; Rashighi et al., 2014).”

“The CXCR3 chemokine system also plays important roles in the positioning of T cells within secondary lymphoid organs and peripheral tissue, facilitating the interactions of T cells with antigen-loaded activated dendritic cells (DCs), promoting T cell activation and differentiation, as well as assisting the process of…”

“CD103+ DCs excel in the priming and cross-presentation of cell-associated antigens to CD8+ T cells and are critical for the efficacy of anti-PD-1 cancer therapy (Salmon et al., 2016; Sánchez-Paulete et al., 2016).”

“The CXCR3 chemokine system also plays important roles in the positioning of T cells within secondary lymphoid organs and peripheral tissue, facilitating the interactions of T cells with antigen-loaded activated dendritic cells (DCs), promoting T cell activation and differentiation, as well as assisting the process of…”

“Correlative human studies have highlighted the potential importance of chemokines for T cell infiltration into tumors and for patient survival (Bindea et al., 2013; Messina et al., 2012).”

“DCs play a critical role in orchestrating T cell responses and can generally be divided into two functionally specific subsets: CD103 DCs are efficient at cross-presentation, which is important in the generation of CD8 T cell responses, whereas CD11b DCs are superior in promoting CD4 T helper (Th) cell responses (Dura…”

“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”

“Furthermore, CXCL9 expression is increased in CD103+ DCs in the context of anti-TIM-3 cancer immunotherapy (de Mingo Pulido et al., 2018).”

“CXCR3 and its ligands guide the recruitment of effector T cells into the inflamed peripheral tissue in type 1 inflammatory responses (Dufour et al., 2002; Hancock et al., 2001; Hancock et al., 2000; Harris et al., 2012; Khan et al., 2000; Rashighi et al., 2014).”

“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”

“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”

“CXCR3 and its ligands guide the recruitment of effector T cells into the inflamed peripheral tissue in type 1 inflammatory responses (Dufour et al., 2002; Hancock et al., 2001; Hancock et al., 2000; Harris et al., 2012; Khan et al., 2000; Rashighi et al., 2014).”

“It has been suggested that the efficacy of immune checkpoint blockade relies on T cells already present in tumors, given that FTY720 administration before treatment did not affect the efficacy of immunotherapy (Garris et al., 2018; Siddiqui et al., 2019; Spranger et al., 2014; Wang et al., 2016).”

“The CXCR3 chemokine system also plays important roles in the positioning of T cells within secondary lymphoid organs and peripheral tissue, facilitating the interactions of T cells with antigen-loaded activated dendritic cells (DCs), promoting T cell activation and differentiation, as well as assisting the process of…”

“The CXCR3 chemokine system also plays important roles in the positioning of T cells within secondary lymphoid organs and peripheral tissue, facilitating the interactions of T cells with antigen-loaded activated dendritic cells (DCs), promoting T cell activation and differentiation, as well as assisting the process of…”

“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”

“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”

“In fact, other chemokine systems, such as CCR2, CCR5, CX3CR1, are associated with T cell migration into tumors (Ahrends et al., 2017; Berghuis et al., 2011; Chew et al., 2012; Fridman et al., 2012; González-Martı́n et al., 2011; Harlin et al., 2009; Liu et al., 2015; Mlecnik et al., 2010).”

“Supporting this notion, recent studies showed that expression of CXCR3 chemokines in myeloid cells is required for inducing anti-tumor T cell responses following checkpoint inhibitor treatment in mice (Chow et al., 2019; House et al., 2020).”