the immune system has evolved to protect the host from infections and cancer . typically , the immune system is divided into two categories- innate immunity and adaptive immunity . the innate immune system comes into play immediately after the appearance of antigen whereas the adaptive immune system provides antigen - specific response . in addition to these defense mechanisms , there are unconventional t cells like the gamma delta (  ) t lymphocytes and natural killer t ( nkt ) cells that functionally and phenotypically belong to both the innate and the adaptive immune system and are able to bridge the two123 . in the peripheral circulation of humans , t cells comprise about 1 - 10 per cent of the circulating t cells , though this percentage can rise to as high as 50 per cent at some mucosal sites4 . t cells are involved in combating infectious diseases and have non - redundant capacities in the inhibition of tumour development and progression56 . unlike  t cells ,  t cells do not require the help of conventional major histocompatibility complex ( mhc ) class i and class ii molecules for recognizing the antigens1 . antigen recognition by  t cells is dependent upon the particular variable ( v ) region of the t cell receptor ( tcr ) as opposed to the entire rearranged tcr required by  t cells . t cells expressing v1 are abundantly found at mucosal sites and these respond to the expression of non - classical mhc molecules on the surface of virally - infected or tumour cells789 . v2 + ( v9v2 ) cells are predominantly present in the peripheral circulation and respond to non - peptide phosphoantigens1011 . v9v2 t cells recognizes self and microbial phosphorylated metabolites generated in the eukaryotic mevalonate pathway and in the microbial 2-c - methyl - d - erythritol 4-phosphate ( mep ) or non - mevalonate pathway12 . it was observed that during bacterial and protozoan infections , v9v2 t cells expand to high levels which in some individuals represented the majority of circulating t cells13 . subsequent characterization of the microbial antigens recognized by human  t cells revealed that these are non - proteinaceous in nature and have critical phosphate residues1116 . the v9v2 crystal structure confirmed the presence of a basic , positively charged region in the binding groove that could directly interact with the negatively charged pyrophosphate moiety of the antigen10 . these phosphoantigens are generated during the non - mevalonate and mevalonate pathways utilized by prokaryotic and eukaryotic cells , respectively121718 . various compounds like steroid hormones , cholesterol , many types of vitamins , rubber , etc . are derived from this pathway . there are now many synthetic phosphorylated compounds that are capable of stimulating  t cells like bromohydrin pyrophosphate ( brhpp ) , 4-hydroxy-3-methyl - but-2-enyl pyrophosphate ( hmbpp ) and mono - ethyl pyrophosphate141920 . in addition to phosphoantigens , there are reports on additional ligands for human  t cells . bisphosphonates , especially nitrogen - containing bisphosphonates ( nbp ) are widely used to treat postmenopausal osteoporosis and skeletal malignancies . inhibit the key enzyme farnesyl pyrophosphate synthase ( fpps ) of the mevalonate pathway , thereby upregulating the pool of endogenous ipp . the accumulated ipp activates v9v2 t cells to release inflammatory cytokines interferon ( ifn)- and tumour necrosis factor ( tnf)-. another class of molecules that stimulate v9v2 t cells is alkylamines . these are also present in edible plant products such as tea , wine , apples and mushrooms21 . t cells discriminate transformed tumour cells from healthy cells by the upregulation of self - antigens like heat shock proteins ( hsp ) . the expression of these proteins are increased in tumour cells due to higher metabolism and serves as endogenous danger signals623 . studies from our laboratory have demonstrated that v9v2 t cells recognize hsp60 on oral tumour cells and have the ability to lyse autologous and allogenic oesophageal tumour targets via recognition of hsp60 and hsp702526 . the influx of tils ( tumour infiltrating lymphocytes ) to the tumour site enhances the potential for anti - tumour immune responses . the numbers and types of lymphocytes present in the infiltrate are related to the chemokines produced by both the tumour cells and tissue stromal cells located at the tumour site . for example , breast , cervix and pancreatic tumours as well as ovarian tumour produce cc and cxc chemokines that are important mediators of macrophage and lymphocyte infiltration in those tumours272829 . interestingly , both v1 and v92 t cells display distinct chemokine receptors that bestow these cells the property to migrate to the tumour site . v1 in addition , v92 t cells express nk receptor p1a ( nkr - p1a ) platelet endothelial cell - adhesion molecules ( pecam ) while v1 use nk receptor p1a nkr - p1a for transendothelial migration31 . v1 t cell subsets from the peripheral blood utilize a larger array of adhesion molecules , namely lfa-1 , vla-4 , vla-5 , l - selectin and e7 , to bind to squamous cell carcinoma cells compared to the restricted usage of lfa-1 , l - selectin and cd44v6 by the v2 t cells32 . the mutually exclusive pattern of chemokine receptor expression in both the subsets of  t cells indicates independent mechanism of homing to tumour site that might have an important aspect in cancer immunotherapy . ability of  t lymphocytes to produce abundant proinflammatory cytokines like ifn- , potent cytotoxic effector function and mhc - independent recognition of antigens makes it an important player of cancer immunotherapy . t cells kill many different types of tumour cell lines and tumours in vitro , including leukemia , neuroblastoma and various carcinomas33343536 . accumulation of mevalonate metabolites in tumour cells is a powerful danger signal that activates the  t cells . in normal cells , ipp produced by mevalonate pathway are at a concentration that is insufficient to trigger  t cells response . however , dysregulation of mevalonate pathway in certain tumours leads to production of higher concentrations of ipp , which is sensed by  tcr as a tumour antigen3738 . it was also shown that mrna knockdown of ipp - consuming enzyme , fpps , induced v9v2 t cell stimulation in otherwise non - stimulatory tumour cells39 . t cells are able to recognize and kill many different differentiated tumours cells , either spontaneously or after treatment with different bisphosphonates , including zoledronate . it has been shown that human tumour cells can efficiently present aminobisphosphonate and pyrophosphomonoester compounds to  t cells , inducing its proliferation and ifn- production40 . combination treatment utilizing v9v2 t cells along with chemotherapeutic agents and zoledronate has been shown to induce an increase in the cytotoxic function of  t cells against solid tumour4142 . the ability of  t cells to efficiently kill bisphosphonates treated colon cancer stem cells and ovarian cancer stem - like cells has also been reported3643 . in addition to phosphoantigens ,  t lymphocytes can also be activated by mitochondrial f1-atpase - related structure expressed together with apolipoprotein a - i , which are expressed on the surface of some tumour cells44 . f1-atpase displays characteristic of antigen presentation molecule by binding to the adenylated derivative of ipp and promoting tcr aggregation , cytokine secretion and cytotoxic activity45 . natural killer ( nk ) receptors expressed on  t cells play a crucial role in mediating the anti - tumour response of  t cells . natural killer group 2 , member d protein ( nkg2d ) expressed on v9v2 t cells is critical for tumour recognition and provides activation signals upon binding to non - classical mhc molecules of the mhc class i chain - related molecules ( mic ) and ul-16 binding protein ( ulbp ) families expressed on tumour cells464748 . this ligand binding to nkg2d can affect the release of tnf- , interleukin ( il)-2  receptor ( cd25 ) upregulation and increase cytolytic potential of  t cells47 . ulbp molecules are involved in v9v2 t cells recognition of leukemias and lymphomas49 and also ovarian and colon carcinomas50 . t cells utilizing the v1 chain isolated from tumour - infiltrating lymphocytes can also kill cancer cells . v1  t lymphocytes have been shown to mediate cytolytic activity by recognizing mica , micb or ulbp expressed on cancer cells5152 . t cells resemble nk cells as these also express cd16 ( fcriii ) receptor . upon recognition of phosphoantigens , a subset of v9v2 t cells upregulates cd1653 . it has been reported that cd16 represent activation / memory status of  t cells and these cd16 cells have specific phenotypic features that distinguish these from the cd16 subset . these constitutively express several natural killer receptors ( nkg2a / cd94 ) and high amounts of perforin , but express low levels of chemokine receptors ( cxcr3 , ccr6 ) and ifn-54 . cd16/fcriii receptor binds to fc portion of immunoglobulin g ( igg ) and engagement of cd16 by  t cells leads to antibody - dependent cellular cytotoxicity ( adcc)55 . adcc is a process in which cd16 + effector cells actively lyse tumour cells that have been bound by specific antibodies . several reports have proven that in vitro  t cells respond to activation via cd16 and mediate adcc against tumour with therapeutic anti - tumour monoclonal antibodies ( mabs ) like rituximab , trastuzumab , of atumumab and alemtuzumab355657 . it has also been shown that stimulated  t cells increase the efficacy of trastuzumab in vivo in her2 + breast cancer patients58 . given the potent antitumour effector function of  t cells and broad reactivity to many different types of tumours has raised a great interest to explore their therapeutic potential . an important feature of  t cells is that these favourably kill cancer cells and show low ( if any ) reactivity towards non - transformed cells which makes these very good candidates for cancer immunotherapy50 . the safety and efficacy of  t cell - based immunotherapy have been evaluated in several clinical trials59 . presently , two strategies for  t cells in tumour immunotherapy have been applied . these are the adoptive cell transfer of in vitro expanded  t cells and the in vivo therapeutic application of -stimulating phosphoantigens or aminobisphosphonates together with low - dose recombinant il2 ( ril2 ) . studies carried out in nude mice demonstrated that repeated infusion of  t cells leads to tumour growth arrest60 . another study carried out in scid mice showed the anti - tumour effector functions of nk cells and  t lymphocytes against autologous melanoma cells61 . in one pilot study , patients with b - cell malignancies that failed conventional therapy were treated with intravenous administration of pamidronate and ril2 to stimulate v9v2 t cells in vivo62 . it was observed that in vivo v9v2 t cells were expanded in five out of nine patients ; three out of these five responding patients had partial remissions and one had stable disease . other trials with adoptive transfer of  t cells include patients with advanced cancer like metastatic renal cell carcinoma63 and non - small cell lung carcinoma64 where stable disease was found in 60 and 37 per cent patients , respectively . in these cases , the regimen consisted of ex vivo activation and expansion of autologous v9v2 t cells with either phosphoantigens , such as brhpp or aminobsphosphnates , like zoledronate or pamidronate or their infusion into the patients . aminobisphosphonates have also been used in clinical trials to treat metastatic prostate cancer65 and advanced breast cancer66 where partial remissions have been reported . complete remission of lung metastasis in a patient with renal cell carcinoma has also been reported after adoptive transfer of  t cells67 . it was shown that the patient was disease free for two years without any additional treatment following in vitro activation and expansion of autologous  t cells with hmbpp plus ril2 , combined with the infusion of zoledronate and ril267 . there is also increasing evidence that stimulating  effector t cells can enhance monoclonal antibody - induced cytotoxicity and thereby improve the anticancer effects of mabs . it was found that repeated infusions of phosphoantigens stimulated  t cells and trastuzumab increased the efficacy of  t cells against her-2 breast carcinoma cell lines in vivo58 . in addition , a survival advantage to patients with an increased  t cells following allogeneic stem cell transplantation ( asct ) has been reported . a long - term survival advantage in a group of high - risk acute leukemia patients who recovered with increased number of circulating  t cells following partially mismatched related haematopoietic stem cell transplantation was reported68 . the unique features of human  t cells related to antigen recognition , tissue tropism , lack of antigen processing requirement and cytotoxic function make these ideal candidates for cancer immunotherapy . t cells recognize increased pool of endogenous ipp ( a consequence of dysregulated mevalonate pathway ) in cancer cells , release ifn-/tnf- and mediate cytolyic effector functions . expression of nkg2d receptors provides a selective advantage to  t cells to recognize tumours that express stress induced molecules like mica / b . this property of  t cells can be exploited for immunotherapy as tumours downregulate mhc molecules to evade immune recognition ( fig . ) . one way to exploit  t cells for cancer immunotherapy is the use of synthetic phosphoantigens like brhpp or hmbpp which can act as  tcr agonists . future trials should harness bisphosphonate activated  t cells in combination with chemotherapy or monoclonal antibodies for treatment of solid tumours and haematologic malignancies . mechanism underlying  t cell killing of tumours :  t cell receptor ( tcr ) interacts with isopentenyl pyrophosphate ( ipp ) generated through the mevalonate pathway in tumours . bisphosphonates inhibits farnesyl pyrophosphate synthase ( fpps ) leading to increased endogenous pool of ipp and dimethylalleyl pyrophosphate ( dmapp ) in tumour cells . t cells recognize heat shock proteins ( hsps ) and mhc class i chain - related molecules ( mica / b ) or ul-16 binding protein ulbp expressed on tumour cells via their tcr and natural killer group 2 , member d protein ( nkg2d ) receptors , respectively . t cells can also kill tumour cells through antibody dependent cellular cytotoxicity ( adcc ) . t cells expressing cd16 ( fcriii ) interacts with tumour associated antigens ( taa ) via specific monoclonal antibodies and mediate adcc . cytokines like interferon- ( ifn- ) and tumor necrosis factor- ( tnf- ) released by  t cells can recruit other immune cells ( bystander effect ) .
t lymphocytes represent a minor subset of peripheral blood in humans ( < 10% ) . 
 t cells expressing v9v2 t cell receptor recognise the endogenous pool of isopentenyl pyrophosphate ( ipp ) that is overproduced in cancer cells as a result of dysregulated mevalonate pathway . 
 aminobisphosphonates increase the endogenous pool of ipp in cells by blocking the enzyme farnesyl pyrophosphate synthase ( fpps ) of the mevalonate pathway . activated 
 t cells release copious amounts of interferon ( ifn)- and tumour necrosis factor ( tnf)- and exhibit potent anti - tumour activity . 
 combination of  t cells with therapeutic monoclonal antibodies can efficiently mediate antibody dependent cellular cytotoxicity against tumours . 
 these features makes  t cells attractive mediator of cancer immunotherapy . 
 we review here , the basic properties and importance of  t cells in tumour immunity , and highlight the key advances in anti - tumour effector functions of  t cells achieved over the last few years and also summarize the results of the clinical trials that have been done till date . future immunotherapeutic approach utilizing  t cells holds considerable promise for treatment of different types of cancer .