Available online at www.sciencedirect.com
`-,,
`•;;, ScienceDirect
`
`Current Opinion in
`
`Immunology
`
`ELSEVIER
`Features of responding T cells in cancer and chronic infection
`Peter S Kim and Rafi Ahmed
`
`Ever since T cell exhaustion was initially characterized and
`thoroughly analyzed in the murine LCMV model, such a
`functional impairment has been validated in other chronic viral
`infections such as HIV, HGV, and HBV. In tumor immunology, it
`has always been postulated that tumor-reactive T cells could
`also become functionally exhausted owing to the high tumor(cid:173)
`antigen load and accompanying inhibitory mechanisms.
`However, the empirical evidences for this hypothesis have not
`been as extensive as in chronic infection perhaps because
`much of the focus on T cell dysfunction in tumor immunology
`has been, and appropriately so, on breaking or bypassing
`immune tolerance and anergy to tumor/self antigens . On the
`basis of recent reports, it is becoming clear that T cell
`exhaustion also plays a crucial role in the impairment of
`antitumor immunity. In this review, we will comparatively
`evaluate the T cell responses in cancer and chronic infection,
`and the therapeutic strategies and interventions for both
`diseases.
`
`Addre sses
`Emory Vaccine Center, Emory University School of Medicine, 1510
`Clifton Road, At lanta, GA 30322, United States
`
`Corresponding aut hor: Ahmed, Rafi (rahmed@emory.edu)
`
`Current Opinion in Immunology 2010, 22:223-230
`
`This review comes fro m a themed issue on
`Tumour Immunology
`Ed ited by Freda Stevenson and Anna Karolina Palucka
`
`Available o nline 6th March 2010
`
`0952-7915/$ - see front matter
`(0 201 O Elsevier Ltd. All rights reserved.
`
`DOI 10.1016/ j.coi.2010.02 .. 005
`
`Introduction
`The immune system is evolutionarily programmed to
`respond to a variety of foreign pathogens. T he refore it
`is not surprising that a significant part of our current
`u nderstanding of T cell immunity comes from acute
`and chronic viral infections. Analyses using acute viral
`models have led to the elucidation of immunological T
`cell memory, a cardinal property of adaptive immunity, as
`re-exposure co t he same pathogen resulrs in more rapid
`and robust T cell responses f 1-61. O n the contrary, in
`chronic infections, the persistence of viral antigens results
`in dysfunctional T cell responses. Therefore, therapeutic
`vaccines have been designed in hopes of boosting the
`overall immune response against chronic viral infect ions,
`such as HIV [7-9], HBV (10,11 ], and HCV [12-141.
`
`However, the results were not as prom1s111g as initially
`envisioned, indicating that during chronic viral infections,
`there exists an intricate network of regulatory mechan(cid:173)
`that are
`s uppressing the necessary
`immune
`isms
`responses requ ired for pathogen clearance.
`
`Because the important discoveries on immunological
`memory and fu nctional exhaust ion of T cells have been
`made
`in acute and chron ic viral models [1-6,15-
`17, 18••, 19], they serve as practical models for studying
`T cell responses in cancer. Tumor im munology has made
`significant progresses in the past decade, and various
`modalities of cancer immunotherapy have been used to
`determine the extent to which an ti-tumor responses, in
`partic ular the T cell effector function , could he gener(cid:173)
`ated. However, the tu mor microenvironment, like t he
`immunological milieu of ch ronic infection, contains a
`multitude of suppressive mechanisms chat allow tumors
`to escape immu ne su rveillance. Conseq ue ntly, various
`treatment methods in tumor immunotherapy have been
`met with outcomes similar co those seen in chronic
`infections.
`
`T his is a brief review of the features of responding T cells
`in cancer and chronic viral infection. We will look at t he
`extent to wh ich respond ing tumor-reactive and chronic
`viral-specific T cells are similar to and different from each
`other. In addition, we will discuss current immunother(cid:173)
`apeutic treatmen ts for chronic infection and cancer, and
`future treatment strategies to perhaps overcome immuno(cid:173)
`logical harriers that limit the success of tumor and anti(cid:173)
`viral imm unotherapy.
`
`Responding T cells in chronic viral infection
`In chronic viral infection, where antigen and/or inflam(cid:173)
`mation persist, virus-specific T cells exhibit various levels
`of exhaust ion. CD8+ T cell exhaustion was first analyzed
`in chronic LCMV infection of mice [16] and could be
`described in several stages: partial exhaustion I & TI, full
`exhaustion, and delet ion [lS,20,21], in which the h ie r(cid:173)
`archical loss of effector cyroki nes, IL-2, T F -a, and
`IFN--y, and ex vivo cytotoxicity were well-demonstrated.
`Antigen-independent proliferation was also diminished in
`exhausted CD8+ T cells, as they were poorly responsive
`to I L-7 and IL -15 [5]. As for virus-specific CD4+ T cells in
`chronic L CMV infection, these cells, like their CD8+ T
`cell brethren, lost the capacity to produce I L-2 and T NF(cid:173)
`a immediately post-infection and were unresponsive to
`rechallenge with antigen [22]. In addition, they exhibited
`increased p roduction ofim munosuppressive I L- 10 in t he
`spleen and more significa ntly in the liver [22]. It has been
`well-documented that CD4+ T cell he lp is important for
`
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`224 Tumour Immunology
`
`maintaining the functionali ty of C08+ T cells during
`c hronic infections (23,24]. Interestingly, there does not
`seem to he deletion of virus-specific C04+ T cells, albeit
`inactivated, during chronic LCMV infection (22], hence a
`potential for therapeutic restoration of the ir helper func(cid:173)
`tion, which may then increase the CTL response. Last
`hue not the least, T regulatory cells during c hronic in(cid:173)
`fection m inimize t issue damage, hut at the same time, aid
`the establishment of viral persistence (25].
`
`An extensive genome-wide array analysis has been per(cid:173)
`formed on exhausted viral-specific C08+ T cells in
`c hronic LCMV infect ion, compared to effector and mem(cid:173)
`ory C08+ T cells in acute LCMV infection (18""]. O ne of
`the more pronounced results from the analysis was the
`overexpression of m RNA for inhibitory cell-surface mol(cid:173)
`ecules. It had been determined that P0-1 was highly
`expressed during chronic LCMV infection and capable of
`regulating G 0 8+ T' cell exhaustion (19]. This array
`a nalysis also s howed that P0-1 was one of the most
`over-expressed in hibitory receptors by exhausted C08+
`T cells. Other highly-expressed inhibitory receptors men(cid:173)
`tioned in this array analysis were 2B4, CTLA-4, and
`LAG-3. Neither CTLA-4 nor LAG-3 blockade in vivo
`improved virus-specific T cell responses in ch ronic
`LCMV infection f26"l, hut L AG-3, a nd not CT LA4,
`blockade, showed synergy with P0-1 blockade (26"].
`Furthermore, when compared to genome profiles of
`memory cells, exhausted C08+ T cells exhibited
`decreased expression of cytokine receptors, I L-4 Ra,
`I L-7 Ra, and I L-2 Rf3, and their unresponsiveness to
`IL-7 and IL-15 may he explained by deficiencies in
`cyroki ne sig naling molecu les, Jakl a nd Stat5b (18].
`T he gene array analysis also s howed that exhausted
`C08+ T cells expressed a distinct set of transcription
`factors, exhibited altered gene expression for chemotaxis,
`adhesion and migration, and displayed dramatic
`deficiencies in metabolism and e ne rgy (18""]. Finally,
`certain anergy-associated genes, such as Egr-2, Egr-3,
`a nd grail, were not selectively expressed in exhausted
`C08+ T cells, suggest ing that anergy and exhaustion were
`distinct processes in chronic LCMV infection [18""].
`
`F u nctio nal exhaustion ofT cells was not only observed in
`c hronic LCMV infection hut also has been confirmed in
`other chronic mouse models and human chronic infec(cid:173)
`tions. Tn HIV infection, persistent antigen load has shown
`to he a major cause for impairment of the ability of HIV
`viral-specific C08+ T cells to generate multiple effector
`cytokines and upregulation of P0-1 [27-29]. In vitm
`blockade of the P0-1/PO-L l pathway has shown to
`improve the effector function of not only HIV f27-29]
`hut also HCV-specific (30-32] and H BV-specific (33]
`C08+ T cells, wh ic h also had upregulated levels of
`P0- 1 during infection. Furthermore, IL-10 production
`was all increased in HIV (34,35], HCV (36-38], and HBV
`f39] infections, indicating t hat like chronic LCMV in-
`
`fection, the IL-10/IL- IOR pathway plays a key regulatory
`role in viral persistence. Another inhibitory molecule chat
`has been garnering attention is the 'T im-3 receptor, a
`member of the Tcell lg and mucin family of proteins with
`galectin-9 as its ligand. In C 0 8'• and C04+ T cells of H IV(cid:173)
`infected individuals, Tim-3 was significantly elevated in
`both T cell types (40"]. Similar to P0-1+ C08+ Tcells,
`Tim-3"• C08+ T cells correlated positively with viral load
`and inversely with the number of C04+ T cells d u ring
`progressive H IV infection [40"]. More interestingly, in
`HIV infection, Tim-3+ T cells were identified as a func(cid:173)
`tionally exhausted population d istinct from P0-1 + T
`cells, and Tim-3 blockade restored T cell effector func(cid:173)
`tion (40"]. Subsequent findings of Tim-3 as a regulator of
`T cell exhaustion have also been made very recently in
`HCV f4 1"] and HBV (42"].
`
`Responding T cells in cancer
`Cancer and chronic infection have been often paired
`togethe r owing to their ability to establ ish high antigen
`and immunosuppressive environment. However, a fu n(cid:173)
`damental difference between the two pat hogeneses is
`that viral antigens in general are exogenous and quite
`immunogenic si nce no central tolerance is involved,
`whereas tumor antigens are self-molecules that are
`weakly immunogenic owing to the deletion of high
`avidity T cells during the t hymic selection process.
`Moreover, high avidity cells that have escaped are inac(cid:173)
`tivated by peri pheral tolerance mechanisms. Because of
`the poor immunogenicity of tumor antigens and the low
`functiona l frequency of tumor-reactive T cells, one of t he
`initial methods to overcome these hurdles has been to
`adoptively transfer in vitro stimulated and expanded
`tumor-reactive T cells and observe their anticumor
`responses. It has been s hown that
`tumor-reactive
`C 0 8+ cells with cent ral memory qualities confer betrer
`anti tumor immunity t han their effector memory counter(cid:173)
`parts [43]. Tn addition, I L-2 treated t umor-reactive C08+
`T cells, albe it highly cytolytic, were shorter lived and
`were less efficacious in vivo t han their I L-15-treated
`counterparts, partly owing to their lack of terminal effec(cid:173)
`tor d ifferentiat ion (44]. Interestingly, induct ion of Wnt-
`13-catenin signaling prevented tumor-reactive C08+ T
`cells from different iating into effector cells, but rather
`promoted the development of self-renewing multi potent
`C 0 8+ memory seem cells [45], which exhibited superior
`proliferative and antitumo r properties than both central
`and effector memory T cells.
`
`'Tumor-reactive T cells in hig h tumor an tigen load have
`shown to respond in a n analogous fash ion as viral-specific
`T cells in chronic infection. First, their phenotypic (upre (cid:173)
`g ulation of inhibitory molecules and downregulation of
`cytokine receptors) and functional (loss of production of
`effector cytokines) profiles resemble those of exhausted
`T' cells from chronic infection. For instance, in a retro(cid:173)
`viral-induced murine CM L model, CML-specific Cos·•
`
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`Features of responding T cells in cancer and chronic infection Kim and Ahmed 225
`
`T cells d isplayed upregulation of PD-1 and decreased
`production of IFN-'Y, T F-a, and TL-2 [46•]. Tumor
`infiltrate lymphocytes (TTL) from h uman metastatic-mel(cid:173)
`anoma lesions also exhihite<l similar phenorypic expres(cid:173)
`sion and functional impairment. Both CD8 .. , in particular
`MART-1-specific, and CD4+ TTLs had significantly
`higher expression levels of PD-1 than peripheral hloo<l
`T cells and those from normal tissues [4(t ,4r ]. Pheno(cid:173)
`typic analysis revealed that compared to T cells from
`normal tissues and hloo<l, a large proportion of CD8+
`TILs were CTLA-4 +, which was mainly expressed hy
`PDl + CD8+ TT Ls [4 r ]. Furthermore, CD25 an<l TL-7Ra
`were lacking in POI + CD8+ T I Ls, indicating that these
`cells were unable to proliferate, prod uce effector cyto(cid:173)
`kines, and d ifferentiate into memory cells [47•]. CD4+
`P D-1 TTLs also shared similar phenorypic expression, as
`they upregulate<l CTLA-4 and lacked CD25 [47•].
`Lastly, the impairment of effector function of PD-1 +
`CD8+ TILs was evident hy s ig nificant reduction of
`IFN-'Y-pro<luction, compared to that of PD-1- CD8 TT Ls
`[47•]. Another study involving human metastatic mela(cid:173)
`noma has s hown that P D -1 was highly expressed in Y(cid:173)
`ESO-1-specific CDs+ TILs, and that PD-1 blockade
`enhanced the frequency of cytokine-pro<lucing cells
`[48. ]. Besides PD-1 and CTLA-4, LAG-3 has s hown to
`he expressed in a suhstantial n umber of C D8+ TILs in
`cancer patients and tumor-hearing m ice [49,50]. As men(cid:173)
`tioned p reviously, T im-3 has heen shown to he upregu(cid:173)
`late<l on exhausted T cells in several chron ic infections. In
`tumor settings, it has yet to he determined the extent to
`which Tim-3 is expressed in TI Ls and regulates the T
`cell effector function.
`
`In chronic viral infection, high antigen load is the major
`driving force in T cell dysfunction through funct ional
`exhaustion, but in cancer, a ne rgy also influences the
`impairment of T cell function (Figure 1). First, tumor
`cells themselves are poor APCs as they a re incapahle of
`expressing costimulatory molecules to provide the second
`signal, rendering T TLs anergic. Immat ure myeloi<l(cid:173)
`<lerive<l <len<lritic cells (M DC) [51 ], plasm acytoi<l DCs
`(PDC) [52], myeloi<l-<lerive<l suppressor cells (MDSC)
`(53] and tumor-associated macrophages (T'AM ) [54] have
`also shown to he potent inducers of T -cell anergy. Ir has
`heen suggested that induction of antigen-specific T' cell
`anergy is an early event in the course of tumor progression
`and significantly occurs before the immunosuppression
`generally seen in advanced tumor hur<lens [55]. On the
`contrary, a nother study has demonstrated that highly
`imm unogenic tumor growth created antigen overload,
`causing functional exhaustion and rapid elimination of
`tumor-reactive T cells [56]. 'Therefore, from a temporal
`standpoint, T cell anergy may he dominant early on, hut
`T cell exhaustion prohahly plays crucial roles in the later
`stages of tumor progression (Fig ure 2). As stated pre(cid:173)
`viously, the gene expression profile of T cell exhaustion
`has shown to he d istinct from anergy in chron ic LCMV
`
`Figure 1
`
`Chronic infection
`Exhaustion/
`Deletion
`
`l
`
`T
`
`lmmunosuppressive
`environment
`
`Exhaustion/
`Deletion
`
`l
`
`Anergy ---j
`
`1-- Central/
`peripheral
`tolerance
`
`T
`
`lmmunosuppressive
`environment
`C urrent Opinion in Immunology
`
`Comparison of T cell dysfunction between chronic infection and cancer.
`In chronic infection, T cell dysfunction mainly occurs through functional
`exhaustion driven by high antigen load. In addition, there is an increased
`level of IL- 10-mediated and Treg-mediated immunosuppression of T
`cells. In cancer, f unctional exhaustion and immunosuppressive
`environment also negatively influence antitumor T cell responses, but
`there are additional factors that contribute to T cell dysfunction. Since
`most t umor antigens are endogenous, tumor-reactive T cells are
`inherently influenced by central and peripheral tolerance mechanisms.
`Anergy also plays a major part in T cell impairment in cancer. For
`example, t umor cells lack costimulatory molecules and are unable to
`provide the second signal to Tlls during direct priming, and various
`antigen presenting cells in the tumor m icroenvironment have shown to
`induce T cell anergy.
`
`infection [18]. Thus, a similar analysis at different rime
`poi nts of tumor progression will reveal the extent to
`whic h TILs are anergize<l and/or exhausted at each
`pathogenic stage, and the results may have important
`therapeutic implications. For example, if T T Ls predomi(cid:173)
`nantly show the molecula r signature of funct io nal exhaus(cid:173)
`tion in advanced tumor hur<lens, immunotherapeutic
`modalities that have shown success in chronic viral infec(cid:173)
`tions could provide similar therapeutic efficacy in cancer
`patients particularly in the later phases of their illnesses.
`
`Therapeutic interventions for cancer and
`chronic viral infection
`For chronic viral infection, therapeutic interventions aim
`to counter the effects of the im mu nosuppressive environ(cid:173)
`ment and high antigen load. One approach for boosting T
`cell responses <luring ch ronic infection is therapeutic
`vaccination (e.g. recombinant vaccinia vaccine, D NA
`vaccine, peptide vaccine, DC vaccines, etc.), which is
`to modulate host immune responses in a n antigen specific
`manner by providing a better stim ulus for virus-specific T
`cells. For the most part, the effectiveness of therapeutic
`vaccines for HIV, HBV, and HCV, as stated p reviously,
`has not heen as strong as initia lly expected. Therefore,
`therapeutic vaccination in combination anothe r immune (cid:173)
`based modality may prove to he a more effective strategy
`to achieve add itive or synergistic efficacy. For instance,
`
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`226 Tumour Immunology
`
`Figure 2
`
`Central tolerance
`
`•
`
`Vlrus•speeiflc
`T cell•
`
`0 ::~~=~'.;.,,,.
`
`Chronic infection
`
`RestoreT
`cell function
`(i.e. PD-1 or
`PD-1/LAG-3
`
`p r I
`ar 18
`
`F II
`u
`
`Deletion
`
`Acute phase
`
`Chronic phase
`
`tolerance
`
`Anergy
`
`Exhaustion/
`Deletion
`
`.
`
`•
`
`tolerance & aner-
`gy (i.e. Treg depl- Cancer
`etion, CTLA-4 bl·
`
`•. - ··=·=·f"i' ~ ..... .,00:- e·'"·""'" - •
`• •••
`•
`•••
`• ••
`lBreak peripheral
`0 Peripheral
`_:·:o-o -0
`
`In situ cancer
`($~98 Q)
`
`Invasive cancer (stages I-IV)
`
`Comparison of T cell dynamics between chronic infection and cancer. In chronic infection, antigen load primarily drives T cells to hierarchical
`exhaustion and ultimately deletion. In cancer, tumor/ self-reactive T cells are initially kept in check by central and peripheral tolerance. Anergy is
`believed to occur immediately in tumor pathogenesis perhaps as early as in in situ cancer, whereas exhaustion/deletion most probably affects T cell
`function in more invasive cancer stages. One of the main purposes of tumor immunotherapy is to break immune tolerance and anergy. Treg depletion
`and CTL.A-4 blockade can unleash tumor-reactive T cells for a potent antitumor response, b ut exhaustion/deletion may ultimately limit the treatment
`efficacy. Therefore, the therapeutic strategies used in chronic infection to rescue T cells from exhaustion, such as PD-1 or PD-1 plus LAG-3 blockade,
`also should be considered in tumor immunotherapy.
`
`C urrent Opinion in Immunology
`
`the combination of LCMV GP33-encoding vacc1111a
`vaccine a nd anti-PD-L 1 blocking antibody significantly
`improved viral-specific CDS+ T cell immunity and con(cid:173)
`sequently decreased viral load in chronic LCMV infec(cid:173)
`tion, compared to either modality alone [57•]. S im ilar
`e nhancement of antiviral T cell responses was seen upon
`neutralization of IL-10, followed by administration of
`D A vaccine encodi ng LCMV antigen [5s•J.
`
`J ust as in chronic infection, therapeutic vaccines have
`been develo ped against cancer to increase the effector
`function of endogenous tumor-reactive T cells. To
`increase the activation of these T cells, cancer vaccines,
`in numerous tumor-hearing hosts, have been paired with
`modalit ies that break intrinsic inhibitory elements and/or
`counter the immu nosuppressive tumor microenviron(cid:173)
`ment. For instance, a combinatorial treatment, using
`HE R-2/neu-targeted vaccine cells that are retrovirally
`transduced to secret GM-CSF (GVAX) for enhancing
`DC recruitment/cross-priming and cyclophosphamide to
`deplete T
`regulatory cells, has resulted in increased
`activation of hig h avidity CDS+ T cells [59]. Similarly,
`GV AX using irradiated tumor cells combined with
`CTLA-4 [60] or PD-1 [6 1•1 blockade s ig nificantly poten-
`
`tiated tumor-reactive T cells compared to either the
`vaccine or the antibody treatment alone. Besides GM(cid:173)
`CSF, Fms-like tyrosi ne kinase 3 ligand (Flt3L), which
`supports the survival, proliferation, and differentiation of
`hematopoietic progenitors, and induces and chemoat(cid:173)
`tracts DCs, has also exhibited similar synergy with
`anti-CTLA-4 antibody when it was retrovirally trans(cid:173)
`duced into tumor cells used for vaccination [62•1. Other
`cancer vaccines utiliz ing vaccin ia virus, peptides, DNA,
`and dendritic cells, all of which have been used for
`chronic viral infection, have also shown prom ise in en han(cid:173)
`cing a ntitumor immun ity and generating better T cell
`responses especially when some were combined with
`CTLA-4 blockade [63,64] or 4-lBB stimulation [65].
`
`Much of combination tumor immunotherapy have cen(cid:173)
`tered on cancer vaccines plus one of the following mod(cid:173)
`inhibitory
`receptors, activating
`alities of blocking
`costimulatory receptors or depleting 'Tregs. This type
`of combination treatments arose out of necessity to
`unleash endogenous tumor/self-reactive T cells from
`the regulatory checkpoints, thereby potentiating the ef(cid:173)
`ficacy of the vaccines. It is interesting that such combi(cid:173)
`nation pai rings have not been fully explored for adoptive
`
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`Features of responding T cells in cancer and chronic infection Kim and Ahmed 227
`
`T cell therapy because the addition of an immunomo(cid:173)
`d ulating agent may significantly improve its efficacy. One
`example is the augmented therapeutic efficacy of adop(cid:173)
`tive T cell therapy when combined with agonistic anti-4 -
`1 BB mAb in a <lose dependent manner f66]. In light of the
`negative correlation between prolonged in vitro culture of
`tumor-reactive T cells and their in vivo function [67,68],
`the evidence of superior antitumor immun ity generated
`by adoptively transferred effector cells derived from na"ive
`rather than cent ral memory CD8+ T cells [68], and the
`need to investigate in vivo priming of adoptively trans(cid:173)
`ferred na°Ive T cells, perhaps now is the time to explore
`various combinatio n treatments centered around adop(cid:173)
`tive T cell therapy.
`
`Even though numerous studies on CTLA-4 b lockade as a
`therapeutic modality for cancer has shown promise in
`enhancing T cell responses, it has had mixed results in
`chronic infection. In in vitro settings, blockade of the
`CTLA-4 inh ibitory pathway a ug mented HIV-specific
`CD4+ T cell function f69] and exhibited synergy with
`PD- 1 blockade in restoring intrahepatic HCV-s pecific
`CD8 ... T cell exhaustion [70]. However, in chronic
`LCMV-infected mice, a nti-CTLA-4 treatment had no
`effect on T cell function and viral control in vivo, whereas
`P D- 1 blockade rescued T cells from functional exhaus(cid:173)
`tion and reduced t he virus load [19]. F urthermore, in the
`L CMV murine model, CTLA-4 deficient mice following
`virus infection showed no sign ifica nt alteration in regulat(cid:173)
`ing viral-specific immunity [71]. In the SIV macaque
`model, which is a closer in vivo reflection of human
`HIV d isease than muri ne LCMV infection, CTLA-4
`blockade not only was unable to improve viral-specific
`T cell responses, but also increased viral replication at
`mucosa! sites [72•], whereas the treatment with partially
`humanized mouse anti-h uman PD-1 Ab enhanced SIV(cid:173)
`specific immunity and showed reductions in the viral load
`[73•]. T his d isparate in vivo efficacy between CTLA-4 and
`P D- 1 blockade in chronic infections compared to cancer
`possibly s uggests that the inductive mechan isms of T cell
`dysfunction differ between chron ic infection and cancer.
`
`Conclusions
`The phenotypic, functional, and molecular changes that
`occur in T cell exhaustion have been extensively ana(cid:173)
`lyzed in chronic v iral infect io ns, which have served as a
`practical model for T cell dysfunction during tumor
`growth and pathogenesis. Some of the key features of
`exhausted T cells in chronic infect ion are exhibited in
`TILs, in particular upregulation of the inhibitory receptor
`PD- 1 and loss of production of effector cytokines. The
`initial aim of tumor immunotherapy has been to break
`immunetolerance and a nergy, but the efficacy of th is
`strategy may now be lim ited by T cell exhaustion
`( F igure 2). T he discovery of PD- I as a major regulator
`and its blockade as a potent rejuvenator ofT cell exhaus(cid:173)
`tion has translated into cli nical cancer trials. Recently, a
`
`p hase I/II clinical trial using an ti-PD- 1 h uman mAB
`M DX- 1106 has been conducted in p atients with various
`solid tumors, and the antibody treatment induced clin ical
`responses against renal cell carcinoma and melanoma
`with well-tolerable s ide effects [JR Brah mer et al., abstract
`in ASCO Annual Meeting 2009, No. 3018]. Thus, un(cid:173)
`derstanding T cell responses in c hronic infections has
`helped to broaden our view on the functional dynamics of
`T cells in the tumor microenvironment, and will continue
`to p lay a major role in therapeutic advancement of anti(cid:173)
`viral and tumor immunotherapy.
`
`Ethics in publishing: general statement
`T he authors comply with the Ethics in Publishing.
`
`Conflicts of interest
`The authors have no confl icts of interest.
`
`Acknowledgements
`We t hank Dr Barry T Rouse for helpful comments and SUAAestions. This work
`was supporced hy grams from the National Institutes of Health (to RA).
`
`References and recommended reading
`Papers of particular interest, published w ithin the annual period of
`review, have been highlighted as:
`
`• of special interest
`.. of outstanding interest
`
`1. Kaech SM, Ahmed R: M em ory CDS+ T cell differentiation: initial
`antigen e ncounte r triggers a developmental program in naive
`cells. Nat lmmunol 2001, 2:415-422.
`
`2. Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R:
`Selective expression of the interleukin 7 receptor identifies
`effector CDS T cells that give rise to long-lived memory cells.
`Nat lmmunol 2003, 4:1 191 -1 198.
`
`3. Kaech SM, Hemby S, Kersh E, Ahmed R: M olecular and
`functional p rofiling of m em ory CDS T cell differentiat ion . Ce//
`2002, 111 :837-851.
`
`4. Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM,
`Antia R, von Andrian UH, Ahmed R: Lineage relationship and
`protective immunity of memory CDS T cell subsets. Nat
`lmmunol 2003, 4:225-234.
`
`5. Wherry EJ, Ahmed R: M emory CDS T-cell differentiation during
`viral infection. J Virol 2004, 78:5535-5545.
`
`6. Sarkar S, Katia V, Haining WN, Konieczny BT, Subramaniam S,
`Ahmed R: Functional and genomic profiling of effector CDS T
`cell subsets with distinct memory fates. J Exp Med 2008,
`205:625-640.
`
`7. OxeniusA, Price DA, GOnthard HF, Dawson SJ, Fagard C, Perrin L,
`Fischer M , Weber R, Plana M , Garcia F etal.: Stimulation of HIV(cid:173)
`specif ic cellular immunity by structured treatment interruption
`fails to enhance viral cont rol in chronic HIV infection. Proc Natl
`Acad Sci US A 2002, 99:13747-13752.
`
`8. Markowitz M, Jin X, Hurley A, Simon V, Ramratnam B, Louie M ,
`Deschenes GR, Ramanathan M Jr, Barsoum S, Vanderhoeven J
`et al.: Discontinuation of antiretroviral therapy commenced
`early during the course of human immunodeficie ncy virus type
`1 infection, with or without adjunctive vaccination. J Infect Dis
`2002, 186:634-643.
`
`9.
`
`Lindenburg CE, Stolte I, Langendam MW, Miedema F, Williams IG,
`Colebunders R, Weber JN, Fisher M, Coutinho RA: Long-term
`follow-up: no effect of therapeutic vaccination with HIV- 1 p17/
`p24:Ty virus-like particles on HIV-1 disease progression.
`Vaccine 2002, 20:2343-2347.
`
`www.sciencedirect.com
`
`Current Opinio n in Im muno logy 2010, 22:223-230
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`228 Tumour Immunology
`
`10. Michel MLPS, Brechot C, Tiollais P: lmmunotherapy of chronic
`hepatitis B by anti HBV vaccine: from present to future. Vaccine
`2001, 19:2395-2399.
`
`11. Mancini-Bourgine M, Fontaine H, Scott-Algara D, Pol S, Brechot C,
`Michel M L: Induction or expansion of T-cell responses by a
`hepatitis B DNA vaccine administered to chronic HBV carriers.
`Hepatology 2004, 40:874-882.
`
`12. Hoofnagle JH: Course and outcome of hepatitis C. Hepatology
`2002, 36:S21 -29.
`
`13. Stauber RESV: Novel approaches for therapy of chronic
`hepatitis C. J Clin Virol 2006, 36:87-94.
`
`14. Leroux-Roels G, Batens AH, Desombere I, Van Den Steen B,
`Vander Stichele C, Maertens G, Hulstaert F: lmmunogenicity and
`tolerability of intradermal administration of an HCV E1-based
`vaccine candidate in healthy volunteers and patients with
`resolved or ongoing chronic HCVinfection. Hum Vaccin 2005:1.
`
`15. Wherry EJ, Blattman JN, Murali- Krishna K, van der Most R,
`Ahmed R: Viral persistence alters CDS T-cell
`i mmunodominance and tissue distribution and results in
`distinct stages of functional impairment. J Viral 2003,
`77:4911-4927.
`
`16. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M,
`Altman JD, Ahmed R: Viral immune evasion due to persistence
`of activated T cells without e ffector func tion. J Exp Med 1998,
`75:5099-5107.
`
`17. Wherry EJ, Barber DL, Kaech SM, Blattman JN, Ahmed R:
`Antige n-independent memory COB T cells do not develop
`during chronic viral infection. Proc Natl Acad Sci US A 2004,
`101 :16004- 16009.
`
`18. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V,
`•• Subramaniam S, Blattman JN, Barber DL, Ahmed R: Molecular
`signature of CDS+ T cell exhaustion during c hronic viral
`infection. Immunity 2007, 27:670-684.
`The authors perfonned a very thorough comparative analysis of the gene(cid:173)
`expression profiles of exhausted LCMV-specific cos+ T cells from
`chronic infection and functional LCMV-specific effector and memory
`cos+ T cells after acute infection. Their gene profiling data showed an
`extensive amount of molecular features that distinctly differentiated
`exhausted cos+ T cells from the other cell types.
`19. Barber DLWE, Masopust D, Zhu B, Allison JP, Sharpe AH,
`Freeman GJ, Ahmed R: Restoring function in exhausted
`CDS T cells during chronic viral infection. Nature 2006,
`439:682-687.
`
`20. Fuller MJ, Zajac AJ: Ablation of COB and CD4 T cell responses
`by high viral loads. J lmmunol 2003, 170:477-486.
`
`21. van der Most RG, Murali-Krishna K, Lanier JG, Wherry EJ,
`Puglielli MT, Blattman JN, Sette A, Ahmed R: Changing
`immunodominance patterns in antiviral CDS T -cell responses
`after loss of epitope presentation or chronic antigenic
`stimulation. Virology 2003, 315:93-102.
`
`22. Brooks DG, Teyton L, Oldstone MB, McGavern DB: Intrinsic
`functional dysregulation of CD4 T cells occurs rapidly
`following persistent viral infection. J Virol 2005:10514- 10527.
`
`23. Matloubian M , Concepcion RJ, Ahmed R: CD4+ T cells are
`required to sustain CDS+ cytotoxic T-cell responses during
`chronic viral infection. J Viral 1994, 68:8056-8063.
`
`24. Battegay M, Moskophidis D, Rahemtulla A, Hengartner H,
`Mak TW, Zinkemagel RM: Enhanced establishment of a virus
`carrier state in adult CD4+ T-cell-d eficient mice. J Virol 1994,
`68:4700-4704.
`
`25. Keynan Y, Card CM, McLaren PJ, Dawood MR, Kasper K,
`Fowke KR: The ro le of regulatory T cells in chronic and acute
`viral infections. Clin Infect Dis 2008, 46:1046-1 052.
`
`26. Blackbum SD, Shin H, Haining WN, Zou T , Workman CJ, Polley A,
`•
`Betts MR, Freeman GJ, Vignali DA, Wherry EJ: Coregulation of
`CDS+ T cell exhaustion by multiple inhibitory receptors during
`chronic viral infection. Nat lmmunol 2009, 10:29-37.
`This study demonstrated that coexpression of multiple inhibitory recep(cid:173)
`tors resulted in a greater degree of T cell exhaustion and viral infection.
`Their coregulation of cos+ T c ell exhaustion was found to be d istinct and
`
`nonredundant, as co-b