Tumor microenvironment: no effector T cells without dendritic cells
PFIRSCHKE, Christina, et al.
Successful antitumor immunity is thought to require T cell entry into tumors, though mechanisms regulating this process remain unclear. In this issue of Cancer Cell, Spranger et al. indicate that chemokines produced by intratumoral Batf3 dendritic cells are critical for effector T cell recruitment. The findings have implications for immunotherapy.
PFIRSCHKE, Christina, et al . Tumor microenvironment: no effector T cells without dendritic cells. Cancer Cell , 2017, vol. 31, no. 5, p. 614-615
DOI : 10.1016/j.ccell.2017.04.007 PMID : 28486102
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No Effector T Cells without Dendritic Cells
Christina Pfirschke,1Marie Siwicki,1Hsin-Wei Liao,1and Mikael J. Pittet1,*
1Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Successful antitumor immunity is thought to require T cell entry into tumors, though mechanisms regulating this process remain unclear. In this issue ofCancer Cell, Spranger et al. indicate that chemokines produced
by intratumoral Batf3 dendritic cells are critical for effector T cell recruitment. The findings have implications for immunotherapy.
Cancer immunotherapies, including adoptive T cell transfer and immune checkpoint blockade, are based on the principle that tumor-reactive cytotoxic T cells can be harnessed for tumor elimi- nation. Such treatments durably control tumors in some patients (Sharma et al., 2017), but efficacy relies on efficient T cell entry into the tumor bed. Unfortu- nately, tumor infiltration by T cells does not always occur, and we lack a compre- hensive understanding of the mecha- nisms that control this process. In this issue of Cancer Cell, Spranger et al.
(2017) reveal that intratumoral CD103+ dendritic cells (DCs) are the major source of two chemokines, CXCL9 and CXCL10, which promote tumor-reactive effector T cell recruitment.
CD103+ DCs are receiving increased attention because they evidently foster tumor control, in contrast to many other myeloid cell types that can promote can- cer (Engblom et al., 2016). Initial work un- covered that intratumoral CD103+ DCs are critical stimulators of tumor-reactive T cell responses in mice, and increased abundance of their transcripts in human tumors correlates with better clinical outcome (Broz et al., 2014). The develop- ment of CD103+DCs depends on several transcription factors, including basic leucine zipper transcription factor ATF- like 3 (Batf3), which allows one to distin- guish these cells from other myeloid cell populations. More recently, it was reported thatb-catenin signaling activa- tion, a melanoma-intrinsic oncogenic pathway, reduces intratumoral CD103+ DC numbers, which prevents tumor-spe- cific T cell priming (Spranger et al., 2015). Thus, CD103+DCs may not only promote antitumor immunity but may
also be suppressed by cancer cells to evade immune recognition.
The new study by Spranger et al.
indicates that effector T cells—when independently generated outside of the tumor stroma—also require intratumoral CD103+DCs for recruitment to the tumor site. For example, the authors found that adoptively transferred effector T cells failed to control tumors with activeb-cat- enin signaling (i.e., lacking tumor-residing CD103+DCs) even when the T cells were specific for a model antigen (SIY) ex- pressed by cancer cells. Similar findings were observed for memory T cells that were produced endogenously. Here, the experimental approach consisted of im- planting immunogenic SIY+ tumors into mice to generate an SIY-specific endoge- nous T cell response; this response cleared the tumor, leaving an SIY-specific memory T cell pool, which was capable of controlling a subsequent challenge with immunogenic SIY+tumors, but not SIY+ tumors that lacked CD103+DCs. Impor- tantly, the authors identified that failure to control CD103+ DC-deficient tumors was due to effector and memory T cell exclusion from the tumor parenchyma.
As expected, tumors containing CD103+ DCs accumulated T cells effi- ciently. When looking at factors that could contribute to T cell tumor recruitment, the authors found that T cells expressed the chemokine receptor CXCR3, while CD103+ DCs were the predominant source of CXCL9 and CXCL10, which are chemokines known to bind CXCR3.
However, it should be noted that CXCR3 can also be expressed by regulatory T cells (Groom and Luster, 2011). Thus, CD103+DCs are likely to recruit not only effector T cells to the tumor, but also cells
with immunosuppressive function, which could present limitations in other cancer models. Gain-of-function and loss-of- function experiments specifically manipu- lating DC development, recruitment, activation, and chemokine expression further demonstrated that Batf3-depen- dent CD103+DCs must be present within the tumor, be activated, and produce CXCR3 ligands in order for effector T cells to gain access to the tumor and ultimately control cancer (Figure 1).
DCs are often seen as lymph node cells that can present MHC-peptide com- plexes to naive T cells and stimulate these cells to become activated T cells that gain the intrinsic capacity to migrate to periph- eral tissues, where they mediate their effector functions. However, DC-driven orchestration of T cell responses may be more complex than previously antici- pated. In the context of cancer, tumor- draining lymph node DCs may initially prime naive, tumor antigen-specific T cells, while intratumoral DCs may further license migration of the antigen-primed T cell progeny. Additional studies will elucidate whether this conceptual frame- work applies globally across diverse tis- sues and cancer types.
Batf3-driven CD141+ human DCs are functionally homologous to murine CD103+DCs (Haniffa et al., 2012); these cells can cross-present antigens, which is critical for antitumor CD8+T cell priming and activation. Interestingly, Spranger et al. were able to show that expression of Batf3 DC transcripts in human mela- noma tumors positively correlated with expression of the CXCR3-binding chemo- kines CXCL9 and CXCL10, as well as CD8+T cell infiltration. These data sup- port the hypothesis that Batf3 DCs are
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important regulators of T cell recruitment to tumors not only in mice but in humans as well.
Intratumoral Batf3 DC-mediated con- trol of T cell recruitment, if confirmed in patients, could have important implica- tions for immunotherapy. For example, assessing the presence or absence of Batf3 DCs in tumors could become rele- vant for predicting patients’ clinical out- comes and defining beneficial treatment options. It would already be interesting to investigate retrospectively whether pa- tients who failed to respond to cancer im- munotherapies harbored particularly low levels of tumor-infiltrating CD141+DCs.
Turning cold tumor microenvironments into hot T-cell-rich areas should be rele- vant for further improving efficacy of im- munotherapies, as recently shown for immune checkpoint blockade in various murine cancer models (Spranger et al.,
2015; Pfirschke et al., 2016; Tang et al., 2016). Conceivably, therapeutics that drive Batf3 DC recruitment and activation in human tumors could trigger efficient tu- mor infiltration by effector T cells and in- crease the proportion of cancers that respond to immunotherapy.
Harnessing CD103+ DC-dependent biology to improve antitumor responses has already shown success in animal models. For example, in mammary carcinoma, colony-stimulating factor-1 (CSF-1) blockade combined with pacli- taxel increases the fraction of intratumoral CD103+DCs and elevates T cell influx to the tumor (Ruffell et al., 2014). Immuno- genic chemotherapeutics can upregulate TLR4 on lung tumor-residing CD103+ DC-like cells, with TLR4+cells promoting CD8+ T cell tumor infiltration (Pfirschke et al., 2016). Moreover, Fms-like tyrosine kinase 3 ligand (FLT3L) can expand
CD103+DCs, in contrast to granulocyte- macrophage colony-stimulating factor (GM-CSF), which promotes CD103 DCs (Broz et al., 2014).
All of this stresses the potential impor- tance of these DCs for optimizing patient responses through recruitment of potent tumor-reactive T cells and promises new ways to better inform treatment deci- sions for cancer patients. Deciphering this biology signals an era wherein the complexity of the tumor microenviron- ment can be harnessed in combinational approaches, such as targeting DCs to potentiate lymphocytes, in order to over- come limitations of current treatment options.
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Figure 1. For Immune-Mediated Tumor Control, Dendritic Cells First, Effector T Cells to Follow
Immune control of tumor growth relies on tumor-reactive effector T cells, with intratumoral Batf3- dependent CD103+DCs as crucial instigators. These DCs must reach the tumor first—depicted here highest on the podium—as they generate chemokine signals (mainly CXCL9 and CXCL10) that result in effector T cell recruitment to the tumor and, ultimately, cancer control.
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