Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 2775–8. ©2017 AACR.

The TAM (Tyro3, Axl, MerTK) family of receptor tyrosine kinases (RTK) is defined by each member possessing an extracellular combination of two immunoglobulin-like domains and two fibronectin type III repeats, a transmembrane portion, and an intracellular region with intrinsic tyrosine kinase activity. The human TAM genes share similar genomic structures, and their resulting proteins share significant structural similarities, with greatest homology in the tyrosine kinase domain. The apparent molecular weights range from 100 to 140 kDa for Axl and Tyro3 and 165 to 205 kDa for MerTK due to posttranslational modifications, including glycosylation, phosphorylation, and ubiquitination. The established natural ligands for the TAMs are two homologous vitamin K–dependent proteins, Gas6 (all three TAMs), and protein S (Tyro3 and MerTK; ref. 1).

All three TAMs have transforming potential; however, Axl overexpression has most frequently been detected in multiple cancers, and its role in supporting tumorigenesis is well recognized. Axl supports tumor growth and dissemination through positive effects on cell survival, proliferation, migration, and invasion. Alongside these, Axl signaling is also involved in other processes ranging from the differentiation of cells in the erythroid lineage, protecting blood vessels from injury, clearance of apoptotic cells, angiogenesis, hematopoiesis, platelet aggregation, and regulation of proinflammatory cytokine production (2, 3). MerTK is most distinctly recognized for its role in negative regulation of the immune system through its ability to mediate phagocytosis of apoptotic cells (4). Tyro3 has a more restricted tissue expression profile and has been implicated in various roles, including myelination in the brain (5).

Although the TAMs are not strong oncogenes, it is increasingly clear that their overexpression contributes to acquiring resistance to both conventional as well as targeted chemotherapeutics in both solid and blood cancers. Early observations included increased Axl expression with resistance to the small molecule inhibitor imatinib (targets BCR-Abl, c-Kit, and PDGFR) in chronic myelogenous leukemia (CML; ref. 6) and to the chemotherapy drugs doxorubicin, VP16, and cisplatin in acute myeloid leukemia (7). Increased resistance to imatinib due to Axl and MerTK overexpression has also been reported in gastrointestinal stromal tumors (8) and non–small cell lung carcinoma (NSCLC; ref. 9).

MerTK overexpression has been detected in high-grade glioblastomas and its knockdown to result in increased sensitivity to etoposide while, conversely, control cells showed elevated MerTK activation upon DNA damage with increase resistance to etoposide (10). Inhibition of Axl and MerTK also led to increased chemosensitivity to temozolomide, carboplatin, and vincristine in astrocytoma (11), and to cisplatin and vincristine in neuroblastoma (12). Axl was also shown to promote resistance to ALK inhibitors in neuroblastoma through induction of epithelial–mesenchymal transition (EMT; ref. 13). MerTK inhibition by an mAb was able to increase sensitivity to carboplatin in NSCLC due to receptor internalization and subsequent degradation, which led to STAT6, Akt, and ERK1/2 signaling inhibition (14). MerTK was also shown in NSCLC to be essential for increased resistance to erlotinib through the regulation of MAPK and FAK signaling pathways (15).

Knockdown of Axl by short hairpin (sh)RNA has revealed Axl to promote the survival of cutaneous squamous carcinoma cells through Akt activation and inhibition of the proapoptotic Bcl-2 family proteins (16). Recently in melanoma, Tyro3 was shown to regulate the expression of microphthalmia-associated transcription factor, a master regulator of melanocyte development, and to promote tumorigenesis in spite of B-Raf–induced senescence (17). Tyro3 was also shown to promote cell proliferation and chemoresistance in breast cancer (18). In addition, downregulation of both Axl and Tyro3 was able to reverse taxol resistance in ovarian cancer (19).

Increased Axl expression has also been associated with acquired resistance to selective EGFR small-molecule inhibition. In lung cancers, this includes resistance to erlotinib through the induction of an EMT-like state (20), as well as to gefitinib (21). In triple-negative breast cancer cells, expression of Axl was identified as a predictor for lack of response to lapatinib and erlotinib (22). Targeting EGFR antibodies such as cetuximab has also led to resistance in NSCLC and head and neck carcinomas through Axl overexpression, via MAPK signaling (23). Such an association between EGFR and Axl molecular pathways also manifests itself through hetero-interaction between EGFR and Axl molecules, which can diversify downstream signaling pathways beyond those triggered by EGFR alone (24).

The prominent expression and functions of TAM receptors across the immune system also suggests a potential role in mediating resistance to immune checkpoint inhibitors in cancer therapy. TAM receptors are notably expressed in many myeloid immune cells, including macrophages and dendritic cells (DC), and they may cooperate to create an immunosuppressive tumor microenvironment permissive to tumorigenesis (25). MerTK is implicated in the suppression of the M1 macrophage proinflammatory cytokine response, and Axl is required for the termination of Toll-like receptor–dependent inflammatory response in DCs (25). Also, the TAMs have been shown to negatively regulate natural killer (NK) cell functional maturation and normal expression of inhibitory and activating NK-cell receptors (26). Furthermore, TAM receptors promote cancer metastases in vivo through suppression of NK-cell activity, while treatment of wild-type NK cells with a TAM-selective small-molecule inhibitor enhanced antimetastatic NK-cell activity (27). Collectively, these data implicate TAMs as key players in regulation of the innate immune system in the tumor microenvironment and indicate that their targeted inhibition will reverse the immunosuppressive microenvironment. This would in particular be expected to have an impact with use of immune checkpoint blockers in cancer therapy, for example, inhibitors of CTLA-4, PD-1, or PD-L1. The TAMs, in particular MerTK, have been shown to upregulate the immune checkpoint molecule PD-L1 as well as promoting phosphatidylserine-dependent efferocytosis and Akt-mediated chemoresistance in tumor cells (28). Therefore, targeting TAM receptors in combination with immune checkpoint blockers could both enhance the latter's efficacy as well as combat eventual resistance. In support of this, recent data from mouse models of carcinoma showed the Axl inhibitor BGB324 in combination with immune checkpoint inhibitors to enhance tumor clearance, survival, and tumor infiltration of cytotoxic T cells (29).

Other influences that can contribute further to TAM-mediated tumor chemoresistance could include increased expression of TAM ligands, although this is not clear. Gas6 expression has been identified as a marker for poor overall survival in ovarian cancer (30). Also, galectin-3, a sugar-binding protein that has been implicated in cancer cell behaviors (31), was indicated to be a novel ligand for MerTK (4). Axl expression has also been correlated with markers of DNA repair in different solid cancers; Axl inhibition induced reversal of EMT and decreased expression of DNA repair genes, rendering cancer cells sensitive to PARP inhibition in a synergistic manner (32).

In addition to their roles in primary tumorigenesis, the prevalence of TAM receptors in patients displaying acquired drug-resistant tumors renders the TAMs a viable target for therapies against such evolved tumors. Importantly, TAM signaling inhibition sensitizes cells to chemotherapy, indicating that its effects are multifaceted, and the aim of “shutting down” multiple key biological processes in cancer cells can be achieved through a single target. A plethora of new, more specific, and higher affinity targeting agents are currently under development (Table 1) that may prove to be effective for preventing, delaying, or combating tumor drug resistance.

Table 1.

TAM-selective inhibitors currently in development

NameTarget(s)Development stage
DP3975 Axl Preclinical 
LDC1267 Axl, Tyro3, MerTK Preclinical 
NA80×1 Axl Preclinical 
YW327.6S2 Axl Preclinical 
GL21.T Axl Preclinical 
NPS-1034 Axl, c-Met Preclinical 
UNC1062 MerTK Preclinical 
UNC569 MerTK Preclinical 
BGB324 Axl Phase I clinical trial for NSCLC (NCT02922777), AML (NCT02488408), and metastatic melanoma (NCT02872259) 
BMS777607 c-Met, Ron, Flt-3, Tyro3, MerTK, Axl Phase I clinical trial for advanced and/or metastatic solid tumors (NCT01721148) 
Glesatinib (MGCD265) Axl, c-Met Phase II clinical trial for NSCLC patients with activating mutations in MET (NCT02544633) 
Sunitinib (SU11248) Flt-3, Axl, VEGFR-2, Kit Approved for pancreatic neuroendocrine and gastrointestinal stromal tumor and kidney cancer. 
Cabozantinib VEGFR-2, c-Met, Ret, Kit, Flt-3, Axl Approved for medullary thyroid cancer 
NameTarget(s)Development stage
DP3975 Axl Preclinical 
LDC1267 Axl, Tyro3, MerTK Preclinical 
NA80×1 Axl Preclinical 
YW327.6S2 Axl Preclinical 
GL21.T Axl Preclinical 
NPS-1034 Axl, c-Met Preclinical 
UNC1062 MerTK Preclinical 
UNC569 MerTK Preclinical 
BGB324 Axl Phase I clinical trial for NSCLC (NCT02922777), AML (NCT02488408), and metastatic melanoma (NCT02872259) 
BMS777607 c-Met, Ron, Flt-3, Tyro3, MerTK, Axl Phase I clinical trial for advanced and/or metastatic solid tumors (NCT01721148) 
Glesatinib (MGCD265) Axl, c-Met Phase II clinical trial for NSCLC patients with activating mutations in MET (NCT02544633) 
Sunitinib (SU11248) Flt-3, Axl, VEGFR-2, Kit Approved for pancreatic neuroendocrine and gastrointestinal stromal tumor and kidney cancer. 
Cabozantinib VEGFR-2, c-Met, Ret, Kit, Flt-3, Axl Approved for medullary thyroid cancer 

NOTE: All are small-molecule inhibitors except YW327.6S2, which is an mAb, and GL21.T, which is an RNA aptamer.

Abbreviation: AML, acute myeloid leukemia.

A recent example is from a study that showed Axl to be upregulated in CML patients that had developed resistance to BCR-Abl small-molecule inhibition, including through a T315I mutation in BCR-Abl. The selective Axl small-molecule inhibitor BGB324 inhibited the resistant CML cells independent of BCR-Abl mutational status (33). This example indicates an efficacious employment of Axl inhibition at the earliest signs of resistance development to first-line or targeted therapies.

The broad cellular and tissue expression profile of TAMs and their roles in the maintenance of the bodily organs' normal functions should be a consideration in strategies aimed at inhibiting TAM receptors in cancer therapy. In particular, the role of TAMs in systemic immunity may represent a double-edged sword in terms of clinical outcome in strategies principally aimed at bolstering antitumor immunity. Both Axl and MerTK are expressed on multiple immune cells, such as DCs and macrophages and have an essential immunosuppressive role via the abrogation of Toll-like receptor and cytokine receptor signaling. Sustained immune activation and chronic inflammation occurs in TAM triple knockout mice (34), and some cytokine receptor signaling systems appear codependent on TAM receptors (35). In addition, one or more of the TAM receptors is a key gateway for phagocytic clearance of apoptotic cells or fragments, as observed in retinal degeneration due to MerTK impairment and hence defective uptake of photoreceptor outer segments by the retinal pigment epithelium (36). Experimental MerTK blockade has also been shown to result in a greater proportion of DCs with enhanced T-cell activation capacity versus tolerogenic DCs (37). Thus, prolonged TAM inhibition, through blocking clearance of dying cancer cells and their subsequent build-up, could result in adverse immune or inflammatory reactions beyond those specifically directed at the tumor cells. Also, Axl and MerTK double knockout mice displayed enhanced colitis resulting from insufficient neutrophil clearance (25) and an increased production of proinflammatory cytokines favoring a tumor-promoting environment with enhanced colonic polyp formation (38).

Results from current clinical trials with multikinase inhibitors including the TAMs (Table 1) already point to a weakened immune system and accumulation of lymphoid cells. This mirrors that which is observed in TAM knockout mice, in which activation of DCs and macrophages also occurs, as well as clinical signs featured in autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (39). Therefore, therapeutic TAM targeting should consider carefully the possibility of inciting adverse proinflammatory effects that may conversely favor tumor promotion as opposed to a desired antitumor immune response. A particularly effective approach, which warrants clinical trial evaluation, would be TAM inhibition in combination with immune checkpoint blockade to target resistance as well as stimulate antitumor immunity specifically.

The TAM RTKs represent a distinct grouping of novel anticancer targets through their promotion of tumor cell survival, proliferation, invasion, and chemoresistance, as well as suppression of the immune status of the tumor microenvironment. Therefore, therapeutic TAM inhibition may sensitize tumor cells to killing by chemotherapy, radiation, or other targeted agents and, in doing so, may create an even more robust innate immune response, which may enhance immunotherapeutic efficacy in combination with immune checkpoint inhibitors. Although development of autoimmunity is a consideration for any sustained TAM inhibition protocol, nevertheless, the employment of novel selective TAM inhibitors has major potential moving forward in combating anticancer drug resistance for many solid and hematologic malignancies.

No potential conflicts of interest were disclosed.

1.
Hafizi
S
,
Dahlbäck
B
. 
Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily
.
FEBS J
2006
;
273
:
5231
44
.
2.
Hafizi
S
,
Dahlbäck
B
. 
Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases
.
Cytokine Growth Factor Rev
2006
;
17
:
295
304
.
3.
Graham
DK
,
DeRyckere
D
,
Davies
KD
,
Earp
HS
. 
The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer
.
Nat Rev Cancer
2014
;
14
:
769
85
.
4.
Caberoy
NB
,
Alvarado
G
,
Bigcas
JL
,
Li
W
. 
Galectin-3 is a new MerTK-specific eat-me signal
.
J Cell Physiol
2012
;
227
:
401
7
.
5.
Goudarzi
S
,
Rivera
A
,
Butt
AM
,
Hafizi
S
. 
Gas6 promotes oligodendrogenesis and myelination in the adult central nervous system and after lysolecithin-induced demyelination
.
ASN Neuro 2016;8. doi:10.1177/1759091416668430
.
6.
Dufies
M
,
Jacquel
A
,
Belhacene
N
,
Robert
G
,
Cluzeau
T
,
Luciano
F
, et al
Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells
.
Oncotarget
2011
;
2
:
874
85
.
7.
Hong
C-C
,
Lay
J-D
,
Huang
J-S
,
Cheng
A-L
,
Tang
J-L
,
Lin
M-T
, et al
Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia
.
Cancer Lett
2008
;
268
:
314
24
.
8.
Mahadevan
D
,
Cooke
L
,
Riley
C
,
Swart
R
,
Simons
B
,
Della Croce
K
, et al
A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors
.
Oncogene
2007
;
26
:
3909
19
.
9.
Linger
RMA
,
Cohen
RA
,
Cummings
CT
,
Sather
S
,
Migdall-Wilson
J
,
Middleton
DHG
, et al
Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer
.
Oncogene
2013
;
32
:
3420
31
.
10.
Wang
Y
,
Moncayo
G
,
Morin
P
 Jr.
,
Xue
G
,
Grzmil
M
,
Lino
MM
, et al
Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme
.
Oncogene
2013
;
32
:
872
82
.
11.
Keating
AK
,
Kim
GK
,
Jones
AE
,
Donson
AM
,
Ware
K
,
Mulcahy
JM
, et al
Inhibition of Mer and axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity
.
Mol Cancer Ther
2010
;
9
:
1298
307
.
12.
Li
Y
,
Wang
X
,
Bi
S
,
Zhao
K
,
Yu
C
. 
Inhibition of Mer and Axl receptor tyrosine kinases leads to increased apoptosis and improved chemosensitivity in human neuroblastoma
.
Biochem Biophys Res Commun
2015
;
457
:
461
6
.
13.
Debruyne
DN
,
Bhatnagar
N
,
Sharma
B
,
Luther
W
,
Moore
NF
,
Cheung
N-K
, et al
ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT
.
Oncogene
2016
;
35
:
3681
91
.
14.
Cummings
CT
,
Linger
RMA
,
Cohen
RA
,
Sather
S
,
Kirkpatrick
GD
,
Davies
KD
, et al
Mer590, a novel monoclonal antibody targeting MER receptor tyrosine kinase, decreases colony formation and increases chemosensitivity in non-small cell lung cancer
.
Oncotarget
2014
;
5
:
10434
45
.
15.
Xie
S
,
Li
Y
,
Li
X
,
Wang
L
,
Yang
N
,
Wang
Y
, et al
Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer, confirming resistance to erlotinib
.
Oncotarget
2015
;
6
:
9206
19
.
16.
Papadakis
ES
,
Cichon
MA
,
Vyas
JJ
,
Patel
N
,
Ghali
L
,
Cerio
R
, et al
Axl promotes cutaneous squamous cell carcinoma survival through negative regulation of pro-apoptotic bcl-2 family members
.
J Invest Dermatol
2011
;
131
:
509
17
.
17.
Zhu
S
,
Wurdak
H
,
Wang
Y
,
Galkin
A
,
Tao
H
,
Li
J
, et al
A genomic screen identifies TYRO3 as a MITF regulator in melanoma
.
Proc Natl Acad Sci U S A
2009
;
106
:
17025
30
.
18.
Ekyalongo
RC
,
Mukohara
T
,
Funakoshi
Y
,
Tomioka
H
,
Kataoka
Y
,
Shimono
Y
, et al
TYRO3 as a potential therapeutic target in breast cancer
.
Anticancer Res
2014
;
34
:
3337
45
.
19.
Lee
C
. 
Overexpression of Tyro3 receptor tyrosine kinase leads to the acquisition of taxol resistance in ovarian cancer cells
.
Mol Med Rep
2015
;
12
:
1485
92
.
20.
Zhang
Z
,
Lee
JC
,
Lin
L
,
Olivas
V
,
Au
V
,
LaFramboise
T
, et al
Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer
.
Nat Genet
2012
;
44
:
852
60
.
21.
Bae
SY
,
Hong
J-Y
,
Lee
H-J
,
Park
HJ
,
Lee
SK
. 
Targeting the degradation of AXL receptor tyrosine kinase to overcome resistance in gefitinib-resistant non-small cell lung cancer
.
Oncotarget
2015
;
6
:
10146
60
.
22.
Meyer
AS
,
Miller
MA
,
Gertler
FB
,
Lauffenburger
DA
. 
The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells
.
Sci Signal
2013
;
6
:
ra66
ra
.
23.
Brand
TM
,
Iida
M
,
Stein
AP
,
Corrigan
KL
,
Braverman
C
,
Luthar
N
, et al
AXL mediates resistance to cetuximab therapy
.
Cancer Res
2014
;
74
:
5152
64
.
24.
Vouri
M
,
Croucher
DR
,
Kennedy
SP
,
An
Q
,
Pilkington
GJ
,
Hafizi
S
. 
Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells
.
Oncogenesis
2016
;
5
:
e266
.
25.
Paolino
M
,
Penninger
JM
. 
The Role of TAM family receptors in immune cell function: implications for cancer therapy
.
Cancers
2016
;
8
:
97
.
26.
Caraux
A
,
Lu
Q
,
Fernandez
N
,
Riou
S
,
Di Santo
JP
,
Raulet
DH
, et al
Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases
.
Nat Immunol
2006
;
7
:
747
54
.
27.
Paolino
M
,
Choidas
A
,
Wallner
S
,
Pranjic
B
,
Uribesalgo
I
,
Loeser
S
, et al
The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
.
Nature
2014
;
507
:
508
12
.
28.
Kasikara
C
,
Kumar
S
,
Kimani
S
,
Tsou
WI
,
Geng
K
,
Davra
V
, et al
Phosphatidylserine sensing by TAM receptors regulates AKT-dependent chemoresistance and PD-L1 expression
.
Mol Cancer Res
2017 Feb 9
.
doi: 10.1158/1541–7786
.
29.
Wnuk-Lipinska
K
,
Davidsen
K
,
Blø
M
,
Hodneland
L
,
Engelsen
A
,
Kang
J
, et al
Abstract B027: BGB324, a selective small molecule inhibitor of AXL receptor tyrosine kinase, enhances immune checkpoint inhibitor efficacy
.
In
:
Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sep 25–28
;
New York, NY. Philadelphia, PA
:
AACR
; 
2016
.
Abstract nr B027
.
30.
Buehler
M
,
Tse
B
,
Leboucq
A
,
Jacob
F
,
Caduff
R
,
Fink
D
, et al
Meta-analysis of microarray data identifies GAS6 expression as an independent predictor of poor survival in ovarian cancer
.
BioMed Res Int
2013
;
2013
:
9
.
31.
Newlaczyl
AU
,
Yu
LG
. 
Galectin-3–a jack-of-all-trades in cancer
.
Cancer Lett
2011
;
313
:
123
8
.
32.
Balaji
K
,
Vijayaraghavan
S
,
Diao
L
,
Tong
P
,
Fan
Y
,
Carey
JPW
, et al
AXL inhibition suppresses the DNA damage response and sensitizes cells to PARP inhibition in multiple cancers
.
Mol Cancer Res
2017
;
15
:
45
58
.
33.
Ben-Batalla
I
,
Erdmann
R
,
Jorgensen
H
,
Mitchell
R
,
Ernst
T
,
von Amsberg
G
, et al
Axl blockade by BGB324 inhibits BCR-ABL tyrosine kinase inhibitor-sensitive and -resistant chronic myeloid leukemia
.
Clin Cancer Res
2017
;
23
:
2289
300
.
34.
Rothlin
CV
,
Ghosh
S
,
Zuniga
EI
,
Oldstone
MBA
,
Lemke
G
. 
TAM receptors are pleiotropic inhibitors of the innate immune response
.
Cell
2007
;
131
:
1124
36
.
35.
Sharif
MN
,
Šošić
D
,
Rothlin
CV
,
Kelly
E
,
Lemke
G
,
Olson
EN
, et al
Twist mediates suppression of inflammation by type I IFNs and Axl
.
J Exp Med
2006
;
203
:
1891
901
.
36.
Gal
A
,
Li
Y
,
Thompson
DA
,
Weir
J
,
Orth
U
,
Jacobson
SG
, et al
Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa
.
Nat Genet
2000
;
26
:
270
1
.
37.
Wallet
MA
,
Sen
P
,
Flores
RR
,
Wang
Y
,
Yi
Z
,
Huang
Y
, et al
MerTK is required for apoptotic cell-induced T cell tolerance
.
J Exp Med
2008
;
205
:
219
32
.
38.
Bosurgi
L
,
Bernink
JH
,
Delgado Cuevas
V
,
Gagliani
N
,
Joannas
L
,
Schmid
ET
, et al
Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer
.
Proc Natl Acad Sci U S A
2013
;
110
:
13091
6
.
39.
Lemke
G
. 
Biology of the TAM receptors
.
Cold Spring Harb Perspect Biol
2013
;
5
:
a009076
.