A perspective on new immune adjuvant principles: Reprogramming inflammatory states to permit clearance of cancer cells and other age-associated cellular pathologies.

2012·0.22 MB·English

by  Prendergast, George C.

AutOphAgIc punctum
OncoImmunology 1:6, 924-929; September 2012; © 2012 Landes Bioscience
A perspective on new immune adjuvant principles
Reprogramming inflammatory states to permit clearance of cancer cells
and other age-associated cellular pathologies
George C. Prendergast1,* and Richard Metz2
1Lankenau Institute for Medical Research; Wynnewood PA USA; 2New Link Genetics Corporation; Ames, IA USA
Aging entails the accumulation of these candidate adjuvant principles and
neoantigens comprised of aggre- their chemical derivatives is discussed in
gated, oxidized, mutated and misfolded terms of their use in generalized strate-
biomolecules, including advanced-gly- gies to improve the prevention or treat-
cation end projects (AGEs). There is ment of cancer and other age-associated
evidence that the immune system can diseases, as negative modifiers of aging.
recognize and clear cells fouled by these
molecular debris, which contribute to The immune system evolved to protect the
the emergence of cancer and other major host from hostile infections. However, it
age-associated diseases such as athero- is also clear that host immunity benefits
genic and neurodegenerative disorders. from the commensal effects of infectious
However, this process may become organisms, especially from those that
increasingly inefficient with aging, per- inhabit the digestive system. In confront-
haps in part because of an insufficiency ing foreign antigens, the immune system
of adjuvant signals normally associated has evolved molecular systems to interpret
with infection that can program pro- some foreign biomolecules that appear
ductive inflammatory states and prop- widely in infectious organisms as signals
erly orient the immune system toward to stimulate and orient the inflammatory
regenerative healing. Here we propose response. In this role, the Toll-like recep-
conceptual foundations for exploring tor (TLR) system recognizes pathogen-
a small set of infection-associated mol- associated molecular patterns (PAMPs)
ecules as potential immune adjuvants to such as lipopolysaccharide, flagella and
reprogram non-productive inflammatory methylated DNA structures that are com-
states in aging tissues, and to improve mon in the bacterial kingdom. PAMPs
the clearance of cellular pathologies that confer potent actions harnessed in some
engender age-associated disease. The cases historically for vaccine adjuvants,
proposed adjuvant classes include a sub- such as the tuberculin TLR3 ligands in
set of d-amino acids used by bacteria to Freund’s complete adjuvant. Thus, dur-
disrupt biofilms; nucleoside derivatives ing an infection, the immune system not
of N6-methyladenine, which functions only encounters foreign antigens but also
Keywords: adjuvants, inflammation at the core of bacterial dam restriction infection-associated signaling molecules
reprogramming, immune signaling, systems; and derivatives of the galacto- that act as immune adjuvants in the host.
immune activation, immunostimulation syl trisaccharide α-Gal, which invokes This two-armed system to interpret
the hyperacute response in primates. foreignness informs the ultimate stance of
Submitted: 07/02/12
These foreign amino acids, nucleosides the immune system concerning whether
Accepted: 07/04/12
and sugar molecules are generally rare or to tolerate or eliminate the foreignness.
http://dx.doi.org/10.4161/onci.21358 absent in humans, except in association Sterile and sometimes chronic inflam-
with infections by bacteria, protists or mations created by injury, aging or dis-
Correspondence to: George C. Prendergast;
[email protected]: nematodes. A rationale for exploration of ease lack adjuvant signals associated with
924 OncoImmunology Volume 1 Issue 6
AutOphAgIc punctum pOInt-Of-VIew
Table 1. characteristics of novel candidate immune adjuvants
Candidate adjuvant Proposed, molecular targets Proposed cellular targets Source Endogenous function
t cells
B cells
d-amino acids
• Amino acid-tRNA synthetases myeloid cells Bacteria Biofilm disassembly
Leu, met, phe, trp
epithelia
endothelia
• Ectonucleosidases
nucleosides
cD39, cD73 t regulatory cells Bacteria DnA modification- restriction
n6-methyladenine (m6A)
• ATP receptor epithelia protists (dam restriction)
and derivatives
p2X7
• Anti-α-gal
• Galectins protists
α-gal* myeloid cells hyperacute response
galectin-3 nematodes
galectin-1
α-galcer
• CD1d nKt cells Sponge unknown
(α-galactosylceramide)
*galactose-α1,3-galactose-α1,3/4-galactosenAc.
infection. In this case, damage-associated of age-associated disease states such as elucidating these mechanisms during the
molecular patterns (DAMPs), such as the accumulation of foam cells at vascular last decade opens opportunities to re-eval-
heat-shock proteins and HMGB1, that lesions that promote thrombotic events. uate historical perspectives on the nature
are released with cellular lysis, may inter- Could the administration of infection- and use of immune adjuvants, not only for
act with TLRs or other receptors to direct associated biomolecules complement this applications in cancer therapy but also for
inflammatory processes via pathways that inefficiency by reprogramming the inflam- the prevention or treatment of age-associ-
are poorly understood but may differ from matory state stimulated by age-associated ated diseases more generally, in which tol-
those engaged by PAMP signals. One neoantigens? In cancer, there is a long his- erance to neoantigens is also apparent.
major characteristic of sterile inflamma- tory behind this idea, as first recorded in In cancer studies, protist infections
tion associated with cancer and perhaps the modern era of medicine by Chekhov appear to have been much less consid-
aging is a chronic “smoldering” nature in the 1880s with regard to long-observed ered than bacterial infections as a source
which is associated with a subversion of correlations of infections with tumor of foreign biomolecules offering poten-
immunity that impedes the clearance of regressions. In the US after the turn of tial immune adjuvant activity. The pro-
cellular pathology.1 Through their ability the 20th century, Coley investigated this tist kingdom encompasses all single cell
to stimulate the immune system, infec- association carefully, eventually settling eukaryotes, including “animal-like”
tion-associated adjuvant molecules may on a virulent combination of Streptococcus protozoa (e.g., cryptosporidiae, trypano-
correct deficiencies in the clearing poten- pyogenes and Serratia marcescens that somes, toxoplasmae), “plant-like” algae
tial that exists, perhaps inherently due could trigger dramatic regressions in some (e.g., rhotophyta, chlorophyta) and “fun-
to an unselected nature during evolution patients, including those with advanced gal-like” molds (e.g., candida). In devel-
for responses to age-associated cellular metastatic cancer. Controversies about oped countries, human infections with
pathologies that emerge only after repro- this toxic treatment caused it to fall out of protists are not common, due to improved
ductive processes of the host are complete. favor by the 1960s, with new laws enlarg- sanitation. Of relevance to cancer, organ-
Neoantigens are abundant in aging due ing the powers of the FDA at that time, isms in this kingdom exhibit far greater
to the accumulation of oxidized, mutated, allowing it to prevent the use of Coley’s antigenic diversity and variation than
aggregated and generally dysfunctional toxin outside of trials. More recently, bacteria during their life cycles, and some
biomolecules. These neoantigens arouse infection-associated molecules underlying protists (e.g., parasites such as trypano-
the immune system, as illustrated by the the effects Coley observed, which were somes) exploit antigenic variation as effec-
appearance of macrophages at the sites of later better documented, were explored tive strategies to escape immune control,
atherogenic lesions in the blood vascula- further in cancer patients as immune adju- similar to what occurs in cancer immu-
ture, and cells harboring such debris may vants, for example, CpG oligonucleotides noediting. Proposed adjuvant principles
be cleared to some extent. However, the that stimulate TLR9 signaling. However, discussed in this perspective are listed in
absence or insufficiency of infection-asso- it is now becoming increasingly clear that Table 1.
ciated foreign biomolecules at such sites immune adjuvants can be conceptualized
may be associated with the generation of more broadly, to include not only mol- d-amino Acids
chronic low-grade inflammatory states ecules that stimulate the immune system,
that are inefficient in clearing cellular but also those that relieve immune inhibi- Recently, an interesting intersection
pathologies, permitting the development tory mechanisms. Indeed, advances in occurred in unrelated studies of immune
www.landesbioscience.com OncoImmunology 925
modulation and biofilm disruption. septicemia). In this context, it is intrigu- m6A represents the root element in dam
Biofilms are the amyloid fibrous struc- ing that leucine amino acid-tRNA synthe- restriction-modification systems, which
tures used by bacteria to organize com- tase (LeuARS) was defined recently as a regulate virulence and serve as a rudimen-
munities. Disassembly of biofilms by sensor of essential amino acid sufficiency tary immune system.26 Some protists also
Bacillus subtilis, Staphylococcus aureus for mTOR control.11 Thus, it is intrigu- employ m6A in DNA as a protective mear-
and Pseudomonas aeruginosa was found ing to consider whether d-amino acids sure against invading infection. However,
to be mediated by a mixture of d-amino used in the bacterial kingdom to modu- the precise extent and impact of m6A in
acids secreted by many bacteria, includ- late biofilms may exert immune adjuvant eukaryotic DNA is unclear.27 In contrast,
ing d-leucine, d-methionine, d-tyrosine properties through ARS interactions that m6A appears to be broadly expressed in
and d-tryptophan.2 Unlike l-amino acids, could program mTOR-dependent path- eukaryotic RNA, where it clusters mainly
which are synthesized and used univer- ways of inflammatory programming and at 3’UTRs, stop codons and microRNA
sally in protein translation, d-amino acids immune activation. Drawing parallels targets.28 Great interest has emerged in
appear to be synthesized only in the bac- from d-1MT studies, it may be interesting m6A-containing RNAs in studies of
terial kingdom, where their appearance to consider whether the biofilm-disrupt- obesity, which has a major inflamma-
in peptidoglycans that are secreted helps ing compounds d-leucine, d-methionine tory component, because of evidence that
bacteria adapt to changing environmental or d-tyrosine or their methyl derivatives major risk conferred by the FTO gene is
conditions.3 analogous to d-1MT may function as associated with m6A demethylation in
With regard to d-tryptophan, its iden- mTOR regulators or immunomodulators. cellular RNA.29 From an evolutionary
tification as a biofilm-disrupting molecule standpoint, it is intriguing to consider
is interesting because of extensive inves- N6-methyladenine whether the impact of adenosine signal-
tigations of the immune modifier effects ing in immunology might relate to the
of its simple derivative d-1-methyl-trypto- Adenosine is a focus of growing interest as detection of m6A derivatives appearing
phan (d-1MT), a molecule that has been a modulator of host immune responses,12 in bacterial and protist DNA or in certain
studied preclinically and clinically as an but variations in the adenine moiety have RNA contexts. In this regard, it is inter-
small molecule inhibitor of the indole- not been widely considered in terms of esting that N6-methyladenine exhibits a
amine 2,3-dioxygenase (IDO) pathway of their potential immunological impact. In shock-like toxicity in mice (unpublished
immune modulation. Based on its trypto- cancer, there is persuasive evidence that observations). While speculative, m6A
phan catabolic activity, IDO is regarded the benefits of effective chemotherapy represents a rational twist in explorations
as a immunosuppressive principle that relate in part to the autophagy-dependent of how to best exploit adenosine signaling
generates antigenic tolerance, but studies release of ATP from dying cancer cells, for inflammatory reprogramming.
in genetically deficient mice indicate that which can exert an immune adjuvant
IDO might act more directly as a modifier effect on antigen-presenting cells.13-17 α-Gal
of the inflammatory microenvironment Adenosine signaling appears to exert a sig-
in cancer, autoimmune disease and infec- nificant effect on immunoediting during The trisaccharide galactose-α1,3-
tion.4-9 Although the relevant biochemical oncogenesis with potential for therapeu- galactose-β1,3/4-galactose-NAc known
targets of d-1MT in immune modulation tic applications.18 The purinergic receptor informally as α-gal decorates the exterior
have yet to be understood completely, P2X7 is an ATP receptor that has captured of all eukaryotic cells, including protists,
genetic investigations in mice clearly particular attention given its overexpres- with the notable exception of humans, apes
establish the dependence of d-1MT activ- sion in cancer cells and its implication in and Old World primates. In its absence
ity on the IDO pathway.10 In particular, cancer progression.19,20 Ectonucleotidases from humans, α-gal plays an important
recent work demonstrates that nanomolar CD39 and CD73 that degrade ATP/ADP role in triggering the hyperacute immune
concentrations of d-1MT are sufficient to to AMP and AMP to adenosine, respec- response, which was originally identified
restore tryptophan sufficiency signaling tively, are widely expressed in tumors by studies of tissue xenotransplanation.30
to mTOR after tryptophan deprivation and they been implicated in malignant The reasons behind the curious evolution
by IDO (R.M, G.C.P. et al., manuscript progression,21,22 possibly also upon their of this response are uncertain, but it is
submitted). These findings suggest that expression on tumor-derived exosomes.23 tempting to speculate that this trisaccha-
sensors of d-amino acids might exist to These molecules may also function on ride plays an important role in immune
modulate inflammation and immune regulatory T cells (Tregs) and vascular responses to protist infections, since ~1%
status by influencing the activation of cells in the tumor microenvironment.24,25 of all antibodies present in human serum
mTOR, a pivotal player in immune con- In the setting of adenosine signal- recognize α-gal epitopes that are pre-
trol. The evolution of such sensors in the ing, the possible immunological impact sented by any non-human eukaryotic cell
host would be valuable, since biofilm deg- of N6-methyladenine (m6A) should be or eukaryotic cell-derived virus or para-
radation could exert major impact on the considered in the contexts of ribose or site. α-gal is unrelated to the galactose
host as a bacterial community switches deoxyribose forms of adenosine or ATP. moiety found in α-galactosylceramide, a
from a localized organization (e.g., m6A is found in the genomic DNAs of sponge-derived biomolecule that acts as a
abscess) to a dispersed organization (e.g., bacteria, protists and fungi. In bacteria, stimulatory ligand for NKT cells. There is
926 OncoImmunology Volume 1 Issue 6
additional evidence that α-gal can engage framed. Extending the concept that α-gal microbiome as a source of immune adju-
the immune system, based on reports of can be employed as an immune adju- vant molecules. α-gal may be relevant in
delayed but acute allergic responses in vant, the administration of α-gal in the this context as an initial opportunity to
a small number of individuals who con- context of an engineered glycolipid has frame combinations of immune adjuvant
sumed red meat or received treatment been reported to exert not only anticancer molecules that may be evolutionarily rel-
with the anti-epidermal growth factor effects but also to accelerate regenerative evant but normally absent in hosts in
receptor (EGFR) monoclonal antibody healing of burn wounds.35,36 In the lat- modern times due to improved sanita-
cetuximab, which is modified with α-gal ter setting, macrophages but especially tion and antiprotist medicines. While it
due to its production from murine SP2/0 neutrophils were efficiently attracted by is speculative that the candidate adjuvants
cells (which express the α-gal transferase). a topical liposome formulation of the proposed here may be useful to reprogram
In both cases, IgEs specific for α-gal were engineered α-gal glycolipid that increased inflammation in the context of cancer or
implicated in the delayed anaphylactic re-epithelization. These results speak other age-associated disorders, a rationale
response that occurred in these individu- to the potential use of α-gal as an adju- to build new concepts from common
als.31,32 While the mechanisms underlying vant beyond cancer in distinct settings of infection-associated signals that engage
these phenomena are poorly understood, regenerative healing. host immunity is logical. Along with
they underscore the notion that α-gal can In assessing targets for α-gal as an α-galactosylceramide (α-GalCer), a ligand
program a robust immune response. immune adjuvant, there are candi- for NKT cells44 derived from a marine
Strategies to harness endogenous α-gal dates among the galactose-binding lec- sponge (the simplest multicellular organ-
antibodies to generate productive antican- tins known as galectins, the elevation of ism beyond protists), one can consider
cer responses have been pursued, based which is an established cause of tumoral combinations of the amino acid, nucleo-
on engineering α-gal decoration of tumor immune tolerance and progression.37 side and carbohydrate moieties associated
whole cell vaccines for cancer immuno- Direct evidence for galectin-3 binding with prokaryote and protist infections
therapy.33 Clinical tests based on preclini- by α-gal has been presented.38 Galectin-3 discussed above as a “diamond adjuvant”
cal findings appear to validate the efficacy modulates T-cell immunity to promote to immunologically pierce the veil of age-
of such an approach. Results from a Phase immunoescape and metastasis in cancer associated diseases that present an abun-
II clinical enrolling 70 resected pancreatic and its immunohistochemical status has dance of neoantigens, but in the absence
cancer patients treated with a whole-cell been associated with poor prognosis.39,40 of infection-associated elements needed
allovaccine termed HyperAcute Pancreas This galectin has also been implicated for effective immune clearance. Indeed,
that was generated from a mixed panel in epithelial wound healing,41 a setting if the efficacy of chemotherapy and radio-
of human pancreatic tumor cell lines in which α-gal has been shown to exert therapy relates to “vaccinating” properties
have been reported recently.34 Significant beneficial effects.35,36 Galectin-1 has also and ATP release (to stimulate adenos-
increases in survival were associated with been linked to immunoescape in cancer42 ine signaling), it is intriguing to consider
acute inflammatory responses triggered and this molecule may also bind α-gal whether such a “diamond” adjuvant might
by vaccine injection, which appeared to be (G. Rabinovich, personal communica- be combined with low-toxicity vaccines to
sufficient to trigger cross-presentation of tion). Given the widespread expression of reduce reliance on high-toxicity therapeu-
tumor antigens as well as degrade immune galectin-1 in protists and eukaryotes, its tics in cancer treatment. In any case, it is
escape. Notably, several patients who sub- function in hyperacute responses and its clear that better molecular definitions of
sequently relapsed with metastatic disease promising utility in cancer vaccines, α-gal the “flavors” of inflammation are needed
all exhibited complete responses to sal- represents a logical candidate for further to conceptualize how to convert “smolder-
vage chemotherapy.34 This is a remarkable exploration as a general immune adjuvant. ing” chronic inflammations to productive
observation given that relapsed pancreatic clearing inflammations, so the immune
cancer is invariably insensitive to chemo- “Whole-Adjuvant” Combinations system can respond to neoantigen “for-
therapy. While the inflammatory pro- for Exploring the Prokaryotic- eignness” in an infection-like context that
gram triggered by HyperAcute vaccines is Protist Microbiome to Treat Cancer is more evolutionarily relevant.
not well understood, these early clinical and Age-Associated Disease It is striking to consider the remarkable
findings suggests that α-gal may help to boost that suitable adjuvants provided to
durably retrain the immune system in a Coley’s investigations sought to stimulate prophylaxis of infectious disease by vac-
manner that can support effective che- immunity to eradicate tumors, but the cination in the 20th century. By analogy,
motherapy. Another intriguing observa- tools he settled on were derived exclusively similar successes in cancer and age-associ-
tion was eosinophilia in most responding from prokaryotes. Would a consideration ated disease might be assisted in the 21st
patients.34 Eosinophils attack helminth of protist infections have affected his out- century with novel adjuvants that can
infections (nematodes). Thus, produc- comes? It is evident that intestinal nema- permit the immune system to interpret
tive inflammatory responses to α-gal may todes and prokaryotes interact in the gut “sterile antigenic” disorders as “infectious
program the immune system to interpret and that these interactions can impact on antigenic” disorders that immunity has
tumor antigens as a parasite infection, to host immunity.43 However, there has been already evolved to handle. With regard
which a robust response can be suitably little parallel consideration of the protist to cancer, it is tempting to wonder how
www.landesbioscience.com OncoImmunology 927
Coley’s toxin experiments might have Disclosure of Potential Conflicts of Interest engaged in the clinical development of IDO
developed further with the inclusion of G.C.P. declares a conflict of interest as pathway inhibitors and HyperAcute cancer
protists and nematodes in his therapeutic a compensated scientific advisor, grant vaccines. G.C.P. is also an inventor on IDO
studies of bacterial infections in cancer recipient and shareholder with interests in technology patents held by his employer
patients over a century ago. New Link Genetics Corporation, which is that have been licensed by this company.
References 13. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, 26. Wion D, Casadesús J. N6-methyl-adenine: an epi-
1. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer- Ortiz C, Criollo A, et al. Toll-like receptor 4-depen- genetic signal for DNA-protein interactions. Nat Rev
related inflammation. Nature 2008; 454:436-44; dent contribution of the immune system to anti- Microbiol 2006; 4:183-92; PMID:16489347; http://
PMID:18650914; http://dx.doi.org/10.1038/ cancer chemotherapy and radiotherapy. Nat Med dx.doi.org/10.1038/nrmicro1350.
nature07205. 2007; 13:1050-9; PMID:17704786; http://dx.doi. 27. Ratel D, Ravanat JL, Berger F, Wion D.
2. Kolodkin-Gal I, Romero D, Cao S, Clardy J, Kolter org/10.1038/nm1622. N6-methyladenine: the other methylated base of
R, Losick R. D-amino acids trigger biofilm disas- 14. Aymeric L, Apetoh L, Ghiringhelli F, Tesniere A, DNA. Bioessays 2006; 28:309-15; PMID:16479578;
sembly. Science 2010; 328:627-9; PMID:20431016; Martins I, Kroemer G, et al. Tumor cell death http://dx.doi.org/10.1002/bies.20342.
http://dx.doi.org/10.1126/science.1188628. and ATP release prime dendritic cells and efficient 28. Meyer KD, Saletore Y, Zumbo P, Elemento O,
3. Lam H, Oh DC, Cava F, Takacs CN, Clardy J, de anticancer immunity. Cancer Res 2010; 70:855-8; Mason CE, Jaffrey SR. Comprehensive Analysis
Pedro MA, et al. D-amino acids govern station- PMID:20086177; http://dx.doi.org/10.1158/0008- of mRNA Methylation Reveals Enrichment in 3’
ary phase cell wall remodeling in bacteria. Science 5472.CAN-09-3566. UTRs and near Stop Codons. Cell 2012; 149:1635-
2009; 325:1552-5; PMID:19762646; http://dx.doi. 15. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, 46; PMID:22608085; http://dx.doi.org/10.1016/j.
org/10.1126/science.1178123. Ma Y, Ortiz C, et al. Activation of the NLRP3 cell.2012.05.003.
4. Divanovic S, Sawtell NM, Trompette A, Warning inflammasome in dendritic cells induces IL-1beta- 29. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et
JI, Dias A, Cooper AM, et al. Opposing biological dependent adaptive immunity against tumors. Nat al. N6-methyladenosine in nuclear RNA is a major
functions of tryptophan catabolizing enzymes during Med 2009; 15:1170-8; PMID:19767732; http:// substrate of the obesity-associated FTO. Nat Chem
intracellular infection. J Infect Dis 2012; 205:152- dx.doi.org/10.1038/nm.2028. Biol 2011; 7:885-7; PMID:22002720; http://dx.doi.
61; PMID:21990421; http://dx.doi.org/10.1093/ 16. Martins I, Tesniere A, Kepp O, Michaud M, org/10.1038/nchembio.687.
infdis/jir621. Schlemmer F, Senovilla L, et al. Chemotherapy 30. Galili U. The alpha-gal epitope and the anti-Gal
5. Muller AJ, Sharma MD, Chandler PR, Duhadaway induces ATP release from tumor cells. Cell Cycle antibody in xenotransplantation and in cancer immu-
JB, Everhart ME, Johnson BA 3rd, et al. Chronic 2009; 8:3723-8; PMID:19855167; http://dx.doi. notherapy. Immunol Cell Biol 2005; 83:674-86;
inflammation that facilitates tumor progression cre- org/10.4161/cc.8.22.10026. PMID:16266320; http://dx.doi.org/10.1111/j.1440-
ates local immune suppression by inducing indole- 17. Michaud M, Martins I, Sukkurwala AQ, Adjemian 1711.2005.01366.x.
amine 2,3 dioxygenase. Proc Natl Acad Sci U S A S, Ma Y, Pellegatti P, et al. Autophagy-dependent 31. Saleh H, Embry S, Nauli A, Atyia S, Krishnaswamy
2008; 105:17073-8; PMID:18952840; http://dx.doi. anticancer immune responses induced by chemo- G. Anaphylactic reactions to oligosaccharides in red
org/10.1073/pnas.0806173105. therapeutic agents in mice. Science 2011; 334:1573- meat: a syndrome in evolution. Clin Mol Allergy
6. Smith C, Chang M-Y, DuHadaway J, Boulden J, 7; PMID:22174255; http://dx.doi.org/10.1126/sci- 2012; 10:5; PMID:22397506; http://dx.doi.
Sutanto-Ward E, Soler AP, et al. IDO is a nodal ence.1208347. org/10.1186/1476-7961-10-5.
pathogenic driver of lung cancer and metastasis. 18. Stagg J, Smyth MJ. Extracellular adenosine tri- 32. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J,
Cancer Discov 2012; In press. phosphate and adenosine in cancer. Oncogene Morse M, et al. Cetuximab-induced anaphylaxis and
7. Muller AJ, DuHadaway JB, Chang MY, 2010; 29:5346-58; PMID:20661219; http://dx.doi. IgE specific for galactose-alpha-1,3-galactose. N Engl
Ramalingam A, Sutanto-Ward E, Boulden J, et org/10.1038/onc.2010.292. J Med 2008; 358:1109-17; PMID:18337601; http://
al. Non-hematopoietic expression of IDO is inte- 19. Roger S, Pelegrin P. P2X7 receptor antagonism in dx.doi.org/10.1056/NEJMoa074943.
grally required for inflammatory tumor promo- the treatment of cancers. Expert Opin Investig Drugs 33. Rossi GR, Mautino MR, Unfer RC, Seregina TM,
tion. Cancer Immunol Immunother 2010; 59:1655- 2011; 20:875-80; PMID:21619470; http://dx.doi. Vahanian N, Link CJ. Effective treatment of preex-
63; PMID:20640572; http://dx.doi.org/10.1007/ org/10.1517/13543784.2011.583918. isting melanoma with whole cell vaccines expressing
s00262-010-0891-4. 20. Adinolfi E, Raffaghello L, Giuliani AL, Cavazzini alpha(1,3)-galactosyl epitopes. Cancer Res 2005;
8. Scott GN, DuHadaway J, Pigott E, Ridge N, L, Capece M, Chiozzi P, et al. Expression of P2X7 65:10555-61; PMID:16288048; http://dx.doi.
Prendergast GC, Muller AJ, et al. The immunoregu- Receptor Increases In Vivo Tumor Growth. Cancer org/10.1158/0008-5472.CAN-05-0627.
latory enzyme IDO paradoxically drives B cell-medi- Res 2012; 72:2957-69; PMID:22505653; http:// 34. Hardacre J, Mulcahy M, Small W, Talamonti M, Obel
ated autoimmunity. J Immunol 2009; 182:7509-17; dx.doi.org/10.1158/0008-5472.CAN-11-1947. J, Caio M, Safran H, Lenz H, Chiorean E, Vahanian
PMID:19494274; http://dx.doi.org/10.4049/jimmu- 21. Zhang B. CD73: a novel target for cancer immu- N, Link C. Addition of algenpantucel-L immuno-
nol.0804328. notherapy. Cancer Res 2010; 70:6407-11; therapy to standard of care (SOC) adjuvant therapy
9. Xu H, Oriss TB, Fei M, Henry AC, Melgert BN, PMID:20682793; http://dx.doi.org/10.1158/0008- for pancreatic cancer. J Clin Oncol 2012; 30.
Chen L, et al. Indoleamine 2,3-dioxygenase in 5472.CAN-10-1544. 35. Galili U. Conversion of tumors into autologous vac-
lung dendritic cells promotes Th2 responses and 22. Whiteside TL. Disarming suppressor cells to improve cines by intratumoral injection of alpha-Gal glycolip-
allergic inflammation. Proc Natl Acad Sci U S A immunotherapy. Cancer Immunol Immunother ids that induce anti-Gal/alpha-Gal epitope interac-
2008; 105:6690-5; PMID:18436652; http://dx.doi. 2012; 61:283-8; PMID:22146892; http://dx.doi. tion. Clin Dev Immunol 2011; 2011:134020.
org/10.1073/pnas.0708809105. org/10.1007/s00262-011-1171-7. 36. Galili U, Wigglesworth K, Abdel-Motal UM.
10. Katz JB, Muller AJ, Prendergast GC, Prendergast 23. Clayton A, Al-Taei S, Webber J, Mason MD, Tabi Z. Accelerated healing of skin burns by anti-Gal/alpha-
GC. Indoleamine 2,3-dioxygenase in T-cell toler- Cancer exosomes express CD39 and CD73, which gal liposomes interaction. Burns 2010; 36:239-51;
ance and tumoral immune escape. Immunol Rev suppress T cells through adenosine production. J PMID:19501971; http://dx.doi.org/10.1016/j.
2008; 222:206-21; PMID:18364004; http://dx.doi. Immunol 2011; 187:676-83; PMID:21677139; burns.2009.04.002.
org/10.1111/j.1600-065X.2008.00610.x. http://dx.doi.org/10.4049/jimmunol.1003884. 37. Rabinovich GA, Croci DO. Regulatory circuits
11. Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, 24. Feng L, Sun X, Csizmadia E, Han L, Bian S, mediated by lectin-glycan interactions in autoim-
Kim HK, et al. Leucyl-tRNA synthetase is an intra- Murakami T, et al. Vascular CD39/ENTPD1 munity and cancer. Immunity 2012; 36:322-35;
cellular leucine sensor for the mTORC1-signaling directly promotes tumor cell growth by scavenging PMID:22444630; http://dx.doi.org/10.1016/j.
pathway. Cell 2012; 149:410-24; PMID:22424946; extracellular adenosine triphosphate. Neoplasia 2011; immuni.2012.03.004.
http://dx.doi.org/10.1016/j.cell.2012.02.044. 13:206-16; PMID:21390184. 38. Jin R, Greenwald A, Peterson MD, Waddell TK.
12. Ernst PB, Garrison JC, Thompson LF. Much ado 25. Sun X, Wu Y, Gao W, Enjyoji K, Csizmadia E, Human monocytes recognize porcine endothelium
about adenosine: adenosine synthesis and function in Müller CE, et al. CD39/ENTPD1 expression by via the interaction of galectin 3 and alpha-GAL. J
regulatory T cell biology. J Immunol 2010; 185:1993- CD4+Foxp3+ regulatory T cells promotes hepatic Immunol 2006; 177:1289-95; PMID:16818789.
8; PMID:20686167; http://dx.doi.org/10.4049/jim- metastatic tumor growth in mice. Gastroenterology
munol.1000108. 2010; 139:1030-40; PMID:20546740; http://
dx.doi.org/10.1053/j.gastro.2010.05.007.
928 OncoImmunology Volume 1 Issue 6
39. Fukumori T, Takenaka Y, Yoshii T, Kim HR, 42. Ito K, Ralph SJ. Inhibiting galectin-1 reduces murine 44. Terabe M, Berzofsky JA. The role of NKT cells in
Hogan V, Inohara H, et al. CD29 and CD7 mediate lung metastasis with increased CD4(+) and CD8 tumor immunity. Adv Cancer Res 2008; 101:277-
galectin-3-induced type II T-cell apoptosis. Cancer (+) T cells and reduced cancer cell adherence. Clin 348; PMID:19055947; http://dx.doi.org/10.1016/
Res 2003; 63:8302-11; PMID:14678989. Exp Metastasis 2012; 29:561-72; PMID:22484915; S0065-230X(08)00408-9.
40. Newlaczyl AU, Yu LG. Galectin-3--a jack-of-all- http://dx.doi.org/10.1007/s10585-012-9471-7.
trades in cancer. Cancer Lett 2011; 313:123-8; 43. Bancroft AJ, Hayes KS, Grencis RK. Life on the
PMID:21974805; http://dx.doi.org/10.1016/j.can- edge: the balance between macrofauna, microflora
let.2011.09.003. and host immunity. Trends Parasitol 2012; 28:93-
41. Cao Z, Said N, Amin S, Wu HK, Bruce A, Garate M, 8; PMID:22257556; http://dx.doi.org/10.1016/j.
et al. Galectins-3 and -7, but not galectin-1, play a role pt.2011.12.001.
in re-epithelialization of wounds. J Biol Chem 2002;
277:42299-305; PMID:12194966; http://dx.doi.
org/10.1074/jbc.M200981200.
www.landesbioscience.com OncoImmunology 929