Review

Prospects for TIM3-Targeted Antitumor Immunotherapy

Shin Foong Ngiow1,2, Michele W.L. Teng1,2, and Mark J. Smyth1,2

AbstractNew insights into the control of T-cell activation and proliferation have led to the identification of checkpoint

proteins that either up- or downmodulate T-cell reactivity. Monoclonal antibody immunotherapies that arereactive with cytotoxic T lymphocyte antigen 4 or programmed death receptor 1 have shown promisingtherapeutic outcomes in mice and humans with established cancer, highlighting the fact that cancerimmunotherapy using T-cell checkpoint inhibitors is one of the most promising new therapeutic approaches.T-cell immunoglobulin and mucin domain 3 (TIM3) is one of many similar inhibitory molecules that are gainingattention as targets, but it remains relatively poorly studied in oncology. This review discusses our recentprobing of the mechanism of action of anti-TIM3 antibody against established spontaneous and experimentaltumors in mice, in the context of the exciting possibility of rationally combining agents that promote tumor-specific T-cell activation, proliferation, effector function, and survival. Cancer Res; 71(21); 6567–71.�2011 AACR.

Introduction

Effector T cells can kill cancer cells, and the presence oftumor-infiltrating lymphocytes (TIL) is considered to be anindication of the host immune response to tumor antigensand to reflect the dynamic process of cancer immunoediting(1). However, exceedingly strict biologic limits that areimposed on the immune system to prevent excessive T-cellactivation and expansion limit the effectiveness of adminis-tered cancer vaccines. Investigators have developed variousimmunotherapeutic agents to circumvent these biologicrestrictions, including (i) vaccine adjuvants, (ii) dendritic cell(DC) activators and growth factors, (iii) T-cell stimulators andgrowth factors, (iv) immune checkpoint inhibitors, and (v)agents to neutralize or inhibit suppressive cells, cytokines, andenzymes. Alone, each approach will have a limited use incancer treatment, but in combinations dictated by the biologyof the tumor microenvironment, these agents are overwhelm-ingly likely to have an impact.The subject of discussion here is the immune checkpoint

inhibitors that are now leading the way to the routine trans-lation of immunotherapy in cancer patients. During thepast decade, new insights into the mechanisms by whichT-cell activation and proliferation are regulated have led tothe identification of checkpoint proteins that either up- or

downmodulate T-cell reactivity (2, 3). In the presence of activemalignancy, pathophysiologic inhibition of T-cell activity maypredominate over stimulation. Tumor immunotherapy aimsto break effector T-cell anergy and to block suppressive celltypes and ligands, allowing effector cells to exert tumoreradication. Much of the recent excitement in the transla-tional field of tumor immunology and immunotherapy hasbeen generated by the recognition that human immunecheckpoint proteins can be blocked by specific monoclonalantibodies (mAb) in patients. Promising clinical data showingdurable, objective responses and improved survival havealready been generated in melanoma with human antibodiesdirected against cytotoxic T lymphocyte antigen 4 (CTLA-4)and programmed death 1 (PD-1; refs. 4–6). Excitingly, anti-CTLA-4 (ipilimumab) was recently approved by the U.S. Foodand Drug Administration for the treatment of patients withmetastatic melanoma. The experience with anti-CTLA-4therapy and the durable clinical benefit observed provideproof of principle of the effectiveness of antitumor immunemodulation and the promise of future clinical immune modu-latory antibodies.

Encouragingly, many of the therapeutic effects of these 2agents and their mechanism of action were somewhatpredicted by mouse models of cancer and immunity. Severalstudies have assessed the mechanism of action of anti-CTLA-4 mAb in mice (7–9) and more recently in humans(10–12). Anti-PD-1 and anti-PD-L1 mAbs have also beenstudied in some depth in mice and humans (13–15). Themechanism of action of anti-PD-1 and anti-CTLA-4 combi-nations has also been explored in mice (16). CTLA-4 is �30%homologous to the costimulatory receptor CD28 and bindswith higher avidity to its ligands, B7-1 and B7-2, allowingCTLA-4 to promote termination of immune responses bypreventing continued T-cell costimulation and activation.Previous reports have shown that CTLA-4–blocking anti-bodies promote T-cell activation and render T-effector (Teff)cells resistant to T-regulatory cells (Treg). Both CTLA-4

Authors' Affiliations: 1Cancer Immunology Program, Trescowthick Lab-oratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria,Australia; 2Department of Pathology, University of Melbourne, Parkville,Australia

Note: M.W.L. Teng and M.J. Smyth contributed equally to this work.

Corresponding Author:Mark Smyth, Cancer Immunology Program, PeterMacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Victoria 8006,Australia. Phone: 61-3-9656-3728; Fax: 61-3-9656-1411; E-mail:mark.smyth@petermac.org

doi: 10.1158/0008-5472.CAN-11-1487

�2011 American Association for Cancer Research.

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blockade and cell-intrinsic CTLA-4 deficiency have beenshown to decrease the suppressive function of CD4þ Tregs(17). Therapeutic antitumor activity is believed to bereflected by an increase in the tumor infiltrating CD8þ

Teff/Treg ratio. In addition, in a nontumor setting, anti-CTLA-4 mAb was recently shown to enhance CD8þ T-cellmemory formation, function, and maintenance (18). Bycontrast, PD-1 functions via different immune signalingpathways than CTLA-4 and is likely to have a differentspectrum of effects when blocked. PD-1 is expressed onT cells following T-cell receptor activation. Binding ofthis receptor to its cognate ligands, PD-L1 and PD-L2,downregulates signals by the T-cell receptor, promotingT-cell anergy and apoptosis, thus leading to immune

suppression (19). PD-1/PD-L1 blockade results in loss ofperipheral tolerance and the initiation of autoimmunity. It isalso recognized that the PD-1/PD-L1 pathway is an impor-tant element contributing to tumor-mediated immune sup-pression. These observations support the idea that murinepreclinical therapeutic experiments may be an importantguide to the conduct of trials employing abrogation ofimmune checkpoint proteins in T cells in patients.

A variety of other molecules that similarly regulate T-cellactivation are being assessed as targets of cancer immuno-therapy (Fig. 1). One of these inhibitory molecules that hasgained considerable attention recently is T-cell immunoglob-ulin and mucin domain 3 (TIM3), a member of a relativelynewly described TIM family (20). TIM3 was first reported as

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Figure 1. Proposed mechanismsof multiple T-cell checkpointblockade using mAbs to enhanceantitumor immunity. A, continuousand prolonged presentation oftumor antigens by antigen-presenting cells (APC) or tumorcells, coupled with coinhibitorysignaling (galectin-9/TIM3,CD80/CTLA-4, MHC-II/LAG-3,and PD-L1/PD-1), on tumor-infiltrating CD4þ T and CD8þ

T cells results in T-cell exhaustion/tolerance/anergy in the tumormicroenvironment. B, multipleT-cell checkpoint blockaderestores the functions of activatedT cells and enhances theirproliferation, thus promotingantitumor immune responses.The effect of TIM3 blockadeon APCs within the tumormicroenvironment and its rolein modulating tumor immunityrequire further investigation.

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expressed by IFN-g–secreting T-helper 1 (Th1) cells andsubsequently on DCs, monocytes, CD8þ T cells, and otherlymphocyte subsets (21, 22). Binding of TIM3 by its ligand,galectin-9, results in Th1 cell death, suggesting a role for TIM3in negatively regulating Th1 responses (23). Blockade ofTIM3 has been shown to increase IFN-g–secreting T cells(24), and TIM3 expressed on monocytes and macrophageshas also been implicated in phagocytosis of apoptotic cells(25).

Key Findings

To date, few studies have extensively assessed the mech-anism of action of anti-TIM3 mAb against tumors. Instead,investigators have characterized the comparatively defectivecytokine effector function of TIM3þPD-1þ CD8þ T-cell popu-lations in experimental tumors in mice (26) or tumor antigen-specific TIM3þPD-1þ CD8þ T cells in advanced melanoma inhumans (27). Although TIM3 appears to be a potentiallypromising target for cancer immunotherapy, the mechanismof action of anti-TIM3 mAb and its activity alone and incombination with other immunomodulatory mAbs in exper-imental and spontaneous mouse models of cancer have notbeen assessed to any great extent. In 3 different experimentalmouse tumor models (CT26, WT3, and MC38), we recentlyshowed that the therapeutic effect of anti-TIM3 required bothCD8þ and CD4þ T cells (28). In the MC38 tumor model, wefurther showed that IFN-g production from CD8þ T cells iscritical for the efficacy of anti-TIM3 mAb therapy. Althoughanti-TIM3 therapy alone had a modest effect against meth-ylcholanthrene-induced fibrosarcomas, impressively, the com-bination of anti-TIM3 and anti-PD-1 mAbs significantlysuppressed established tumor growth and even resulted incures in a small proportion of these treated mice (28). Theincrease in antitumor effect achieved by combining anti-TIM3with anti-CTLA-4 and/or PD-1 mAbs compared with singletherapy alone was also observed in 6 different experimentalmouse tumor cell lines (28). Of importance, anti-TIM3 alone orin combination with anti-CTLA-4 and/or anti-PD-1 was welltolerated, and no overt autoimmunity was observed in treatedtumor-bearing mice. Overall, our study strongly supports thepotential of blocking TIM3 in combination with other immunecheckpoint inhibitors for the treatment of cancer.

Implications

Previous studies (26, 27) implied that the target of anti-TIM3 therapy might be the TIM3þPD-1þ T-cell populationsfound in established tumors. Of interest, however, in ourstudies, anti-TIM3mAb therapy appeared to be effective whenadministered sometime before the appearance and accumu-lation of significant TIM3þPD-1þ T-cell populations in CT26tumor-bearing mice (28). Early (day 7–11) CT26 subcutaneoustumors contained CD8þTIM3�PD-1� cells but very few de-tectable TIM3þPD-1þ or TIM3þPD-1� T cells, and yet thetumors clearly responded to anti-TIM3 therapy. The apparentlack of TIM3þ T cells early in tumor progression may bemisleading, because the expression of TIM3 may itself be very

transient. However, the target and mechanism of anti-TIM3may also be model dependent, because anti-TIM3 was alsoeffective against establishedMC38 tumorswhere TIM3þPD-1þ

T cells were the predominant T-cell population among TILsat the commencement of treatment. In this model, mainte-nance of the CD8/CD4 ratio of MC38 TILs over time correlatedwith the response to anti-TIM3 mAb (28). However, at thistime, it is not possible to strictly discount TIM3þPD-1� orTIM3þPD-1þ T cells as a possible target of anti-TIM3. Avery recent study supported the exhausted phenotype ofTIM3þPD-1þ T cells in acute myeloid leukemia and showedthat combined blockade of PD-1/PD-L1 and TIM3/galectin-9rescued mice from acute myeloid leukemia lethality (29).

Our studies did not reveal a significant effect of targetingTIM3 on CD11cþ DCs and, instead, showed that the impor-tance of these cells was modest and model dependent (28).However, in addition to binding galectin-9, TIM3 has beenreported to be a phagocytic receptor for apoptotic cells by asubset of macrophages, monocytes, and CD8þ splenic DCs.Thus, the effect of anti-TIM3 mAb on tumor cell death andcross presentation of tumor antigens by DC may be worthyof further exploration (25). In a tumor setting, TIM3 caninduce the expansion of CD11bþLy6Gþ cells in the spleens ofmice implanted with the T-cell lymphoma, EL-4. Treatmentof these mice with anti-TIM3 mAb resulted in delayed tumorprogression and modulation of these cells (30). AlthoughTIM3 ligation induces cell death in CD4þ Th1 cells (23) andexpands CD11bþLy6Gþ cells, paradoxically, similar ligationon DCs can result in the production of proinflammatorycytokines (22, 25, 31), promotion of DC maturation, anddevelopment of antimicrobial immunity (22, 32). Collectively,these findings suggest that TIM3 may play different bio-logic roles in different leukocyte subsets, and unraveling theeffects of anti-TIM3mAb on these subsets will be important forthe development of this approach for cancer immunotherapy.

The effects of anti-TIM3 in combination with anti-PD-1and/or anti-CTLA-4 mAbs against established B16F10, MC38,and CT26 tumors were broad and encouraging (28), and theseapproaches are worthy of further preclinical development inthese and other models to optimize the regimen schedule andfurther understand the mechanism of action of each combi-nation. Anti-CTLA-4 therapy is more effective against mousetumors when administered at the time of tumor inoculation,and it appears comparatively more effective in humans, so ourexperiments may underestimate the potential therapeuticbenefit of these combinations. Established B16F10 tumorsgrow rapidly and are extremely difficult to treat with anysingle therapy. The anti-B16F10 tumor effect achieved withthe anti-TIM3/anti-CTLA-4/anti-PD-1 combination was ap-proximately what we achieved with complete Treg cell deple-tion (33), an intervention that provokes both innate andadaptive arms of antitumor immunity. These data indicatethat targeting CTLA-4, PD-1, and TIM3 can at least be additive,and that each of these pathways has a unique mechanism forpreventing an effective antitumor immune response. Just asimportant, with improved tumor suppression, these combi-nation therapies did not provoke any overt autoimmunity inmice (e.g., vitiligo). Whether this will be the case in humans

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remains to be determined and is of critical importance giventhe impact of completely blocking CTLA-4 in humans, par-ticularly because the mouse models have not been validated topredict autoimmune side effects. Encouragingly, our prelim-inary data regarding combined anti-PD-1 and anti-TIM3treatment of established fibrosarcomas induced de novo bymethylcholanthrene suggest that this combination might beeffective against at least a fraction of tumors (28). A largerstudy with pretreatment biopsy correlating target expressionamong TILs and the genetics of tumors with therapeuticactivity from these immunotherapies in this and other spon-taneous tumor models would be extremely informative. Withthe clinical development of anti-PD-1 and anti-PD-L1 treat-ments in humans that is currently underway, the prospect ofcombining these or anti-CTLA-4 approaches withanti-TIM3 mAb in diseases such as melanoma, prostatecancer, renal cell carcinoma, and sarcoma is very appealing.

Future Directions

To date, mono-immunotherapy using anti-CTLA-4 or anti-PD-1 mAb in humans has shown promising therapeutic out-comes, proving that immunotherapy with T-cell checkpointinhibitors is one of the most promising new therapeuticapproaches. With these new therapies, long-term stabilizationof disease and overall survival of patients may be morevaluable endpoints than classical Response Evaluation Crite-ria in Solid Tumors. In parallel, the identification and charac-terization of multiple T-cell checkpoints through research willdrive the further clinical development of other checkpointinhibitors, such as TIM3 and lymphocyte-activation gene 3(LAG-3). The role of TIM3 expressed on immune cells otherthan DCs and T cells and the potential toxic effects oftargeting TIM3 require further exploration if antihumanTIM3 antibodies are to proceed to clinical development.LAG-3 is located in the CD4 locus (34), and when expressedon activated CD4þ and CD8þ T cells, it negatively regulatesT-cell expansion by inhibiting T-cell receptor–induced calci-um fluxes, thus controlling the size of the memory T-cell pool(34). LAG-3 signaling is important for CD4þ regulatory T-cellsuppression of autoimmune responses, and LAG-3 maintainstolerance to self and tumor antigens via direct effects onCD8þ T cells. A recent study showed that blockade of both

PD-1 and LAG-3 could provoke immune cell activation in amouse model of autoimmunity (35). Taken together, thesedata show a direct role for LAG-3 on CD8þ T cells and may beanother important potential target for checkpoint blockade.

Another attractive alternative is to combine checkpointinhibitors with antibodies or agonists that activate immunecells. The reversal of anergic/exhausted T cells by check-point blockade may allow these cells to be more potentlyactivated and to develop full antitumor effector function.Possible approaches for activating immune cells includethe use of antibodies that target costimulatory receptors(e.g., CD137, OX40, CD40, and glucocorticoid-induced TNFreceptor–related gene); chemotherapeutics or radiotherapyto trigger immunogenic cell death (36); and vaccines/adju-vants to promote adaptive immunity. Antibodies that targetstimulatory molecules, such as CD40 and CD137, have beentested in early-phase clinical trials, and they all have theirown spectrum of side effects to be considered. It will now becritical to extensively test the antitumor efficacy and safetyof combining immunomodulatory therapies (e.g., T-cellcheckpoint inhibitors and T-cell activation agonists) pre-clinically using emerging mouse models of cancer that aremore clinically relevant or in which small-molecule thera-peutics have shown promising activity (e.g., mouse modelsof c-kit mutant gastrointestinal stromal tumor and B-rafmutant melanoma).

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors thank Sumone Chakravarti for a helpful review of the manu-script.

Grant Support

National Health and Medical Research Council of Australia (programgrant 454569, Peter Doherty Fellowship to M.W.L. Teng, and NH&MRCAustralia Fellowship to M.J. Smyth), Prostate Cancer Foundation of Australia,Victorian Cancer Agency, and Cancer Research Institute (PhD scholarship toS. Ngiow).

Received May 5, 2011; revised July 7, 2011; accepted July 12, 2011;published OnlineFirst October 18, 2011.

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