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Turner, S. Targeted Agents for Paediatric ALK-Positive ALCL. Encyclopedia. Available online: https://encyclopedia.pub/entry/17016 (accessed on 05 December 2025).
Turner S. Targeted Agents for Paediatric ALK-Positive ALCL. Encyclopedia. Available at: https://encyclopedia.pub/entry/17016. Accessed December 05, 2025.
Turner, Suzanne. "Targeted Agents for Paediatric ALK-Positive ALCL" Encyclopedia, https://encyclopedia.pub/entry/17016 (accessed December 05, 2025).
Turner, S. (2021, December 12). Targeted Agents for Paediatric ALK-Positive ALCL. In Encyclopedia. https://encyclopedia.pub/entry/17016
Turner, Suzanne. "Targeted Agents for Paediatric ALK-Positive ALCL." Encyclopedia. Web. 12 December, 2021.
Targeted Agents for Paediatric ALK-Positive ALCL
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13236003

Anaplastic large cell lymphoma (ALCL) is a peripheral T cell non-Hodgkin lymphoma (NHL) with an annual incidence of 1.2 per million children aged under 15. The World Health Organisation (WHO) sub-classifies ALCL into anaplastic lymphoma kinase (ALK)-positive nodal/systemic, ALK-negative nodal/systemic, primary cutaneous and breast implant-associated ALCL. The majority of paediatric ALCL is ALK-positive, usually due to a t(2;5) (p23;q35) chromosomal translocation causing the expression of the oncogenic breakpoint product NPM1-ALK.

anaplastic large cell lymphoma resistance chemotherapy paediatric cancer Tyrosine kinase inhibitors Crizotinib NHL Lorlatinib Alectinib Brigatinib

1. Mechanisms of Resistance to ALCL Therapy

It is anticipated that resistance to these novel agents may be a major problem. Understanding how this resistance develops, and how it can be overcome, will be essential to the successful integration of these novel approaches into the mainstream treatment of paediatric ALK-positive ALCL.

2. Mechanisms of Resistance to ALK Tyrosine Kinase Inhibitors

Despite the promise of ALK TKIs, it appears at least in some contexts, that therapy will either have to be for long periods of time or as a bridge to another treatment, as swift relapses have been observed on the discontinuation of crizotinib monotherapy [1][2]. In addition, resistance is expected as has been experienced for patients with ALK-positive NSCLC [3]. Indeed, reports of crizotinib resistance developing within months of treatment initiation in patients with ALCL have been published [4][5].
ALK TKI resistance can either be ALK-dependent or -independent with the former largely occurring due to mutations in ALK (Figure 1 and Figure 2). These have been reported as either mutations in residues at the TKI binding site, or those that result in conformational changes that increase aberrant ALK activity [6][7]. Extensive studies of ALK-dependent resistance mechanisms in NSCLC [3][8] have identified numerous mutations which in some cases are specific to a certain ALK TKI and in others are ubiquitous amongst the ALK TKIs (Table 1). In the treatment of NSCLC, clinicians usually start by treating with crizotinib, and then swap to second- or third-generation inhibitors depending on the ALK mutation that has developed. Ultimately this increases the risk of compound mutations developing, which confer resistance to second and even third-generation inhibitors [3][9]. However, some of these compound mutations can actually re-sensitise patients to crizotinib, even if it has been administered to the patient previously [3]. Cycling of TKIs may therefore be an approach to preventing or responding to the development of resistance.
Cancers 13 06003 g001 550
Figure 1. The NPM1-ALK fusion protein produced due to a t(2;5)(p23;q35) chromosomal translocation. The kinase domain, depicted in red, is the site within the ALK portion of the fusion protein where ALK tyrosine kinase inhibitors (ALK TKIs) bind. Mutations here can lead to ALK TKI resistance [10][11]. AAs = amino acids, TM = transmembrane, TK = tyrosine kinase.
Cancers 13 06003 g004 550
Figure 2. ALK-dependent mechanisms of resistance to ALK TKIs. (A) Mutations in the ALK tyrosine kinase domain prevent the ALK TKI from binding to the receptor and exerting its inhibitory effect on oncogenic ALK signalling. (B) Amplification of the ALK gene provides an excess of drug target outcompeting the inhibitor.
Another form of ALK-dependent resistance is caused by the amplification of the ALK gene (Figure 4). This results in resistance due to a target excess [3][8] as has been reported for NSCLC cell lines [12][13] and patients [8][14][15], as well as ALCL cell lines [16][17] but not yet for ALCL patients. Interestingly, ALK upregulation in response to ALK TKIs results in overwhelming ALK signalling such that if the ALK TKI treatment is stopped, the excess in ALK signalling can counterintuitively drive apoptosis. Therefore, a non-continuous dosing regimen may be beneficial [17][18][19].
Table 1. Summary of reported ALK mutants conferring resistance to ALK TKIs. Sites of the identified mutations are reported according to their position in the full-length ALK protein. Resistance mutations refer to those reported in the context of conferring resistance to ALK TKIs, some of which have been proven to confer sensitivity to ALK TKIs and others with conflicting evidence as to their ALK TKI response. Ins = insertion, del = deletion.
ALK TKI ALK Mutation
Resistance Sensitivity Conflicting
Crizotinib C1156T [20]
C1156Y [3][9][21][22][23][24][25][26]		 L1198F [9][21][27][28]
C1156Y/L1198F [27]		  
  D1203N [9][28][29][30] G1202R/L1198F [23]  
  E1210K [9][22][31] I1171N/L1265F [23]  
  F1174C [6][9][21][23][31]
F1174I [23]
F1174L [32][33]
F1174V [23]
F1245V [24]		    
  G1128A [34]    
  G1202R [8][9][21][22][26]
G1202del [9][21]		    
  G1269A [9][14][21][22][26][28][31]
G1269S [35]		    
  I1171N [9][21][22][35][36][37]
I1171S [9][21][22][35]
I1171T [6][9][21][22][23][24][30]
I1171X [38]		    
  I1268L [23]    
  L1152P [35][39]    
  L1152R [13][26]    
  L1196M [3][8][9][12][14][21][22][23][24][25][26][28][30][31]
L1196Q [23][28][36]		    
  L1198P [29]    
  R1192P [40]    
  S1206C [22][35]
S1206Y [8][9][22][26]		    
  T1151K [41][42]
T1151M [40]		    
  V1180L [28]    
  Q1188_L1190del [43]    
  1151Tins [8][22]    
  D1203N/E1210K [9][21]    
  D1203N/F1174C [9][21]    
  F1174L/G1269A [30]    
Ceritinib F1174L [9][22][35][39][40] E1210K [9][21] C1156Y [9][21][22][35][39][44]
  F1174S [22] F1245C [45] D1203N [9][21][22][28]
  F1174V [35] I1171T [9][21][39] F1174C [9][21][39][44]
  G1123S [46] I1268L [23] G1202R [9][21][22][24][30][35][44]
  G1128A [30] L1196Q [23] G1269A [9][21][28][30][39][40]
  G1202del [9][21][35] S1206Y [39][47] I1171N [9][21][22][39]
  L1122V [28] V1185L [23] I1171S [9][21][22]
  L1152P [35] G1269A/I1171S [48] L1196M [9][21][22][23][28][39][47]
  L1152R [35][39] G1269A/I1171N [23]  
  L1198F [9][21][28]    
  R1192P [40]    
  R1275Q [3]    
  T1151K [41]    
  T1151M [40]    
  T1151Sins [49]    
  Q1188_L1190del [43]    
  1151Tins [35][39]    
  C1156Y/I1171N [9]    
  C1156Y/G1202del/V1180L [9]    
  D1203N/E1210K [9][21]    
  D1203N/F1174C [9][21]    
  E1210K/I1171T [30]    
  G1202R/F1174L [9]    
  G1202R/F1174V [24]    
  G1202R/L1196M [23]    
Alectinib F1174I [23] C1156Y [9][21][50] F1174C [6][9][21]
  F1174L [9][22][23][35][39][40] D1203N [9][21][28] I1171T [6][9][21][22][23][51]
  F1174S [22] E1210K [9][21] L1196M [9][21][22][23][28][50]
  F1174V [23][35] F1174L [50] 1151Tins [50]
  G1202R [9][21][22][24][31][50] G1269A [9][21][28][50]  
  G1202S [31] I1268L [23]  
  G1202del [9][21] L1152R [50]  
  G1210K [52] L1198F [9][21]  
  G1269A [40] L1256F [23]  
  I1171N [9][21][22][23][24] S1206Y [50]  
  I1171S [9][21][22][23][40] T1151K [42]  
  I1171 X [38] V1185L [23]  
  L1122V [28] I1171N/L1256F [23]  
  L1196Q [23]    
  L1198F [28]    
  R1192P [40]    
  T1151M [40]    
  V1180L [51]    
  W1295C [30]    
  D1203N/E1210K [9][21]    
  D1203N/F1174C [9][21]    
  F1174L/G1269A [30]    
  G1202R/L1196M [30]    
  L1196M/V1185L [23]    
Brigatinib G1202L [53] C1156Y [9][21][39] D1203N [9][21][22][28][39]
  G1202del [9][21] F1174C [9][21][39] E1210K [9][21][22]
  L1122V [16][28] F1174L [39] G1202R [54][9][21][22][39]
  S1206C [22] G1269A [28][39] I1171N [9][21][36][39]
  D1203N/F1174C [21] I1171S [9][21][38] L1198F [9][21][28][39]
  D1203N/E1210K [21] I1171T [9][21] S1206Y [3][22][39]
  E1210K/S1206C [21][31][35] L1152P [39]  
  F1174V/L1198F [16] L1152R [39]  
  F1174L/L1198V [31] L1196M [9][12][21][28][39]  
  G1202R/L1196M [55] L1196Q [36]  
    V1180L [28][39]  
    1151Tins [39]  
    G1269A/I1171S [48]  
    G1269A/I1171N [23]  
    I1171N/L1196M [23]  
    I1171N/L1198F [23]  
    I1171N/L1256F [23]  
Lorlatinib C1156F [56] C1156Y [9][21] E1201K [9][21][56]
  G1128S [56] D1203N [9][21] G1269A [9][21][28][57]
  L1256F [23] F1174C [9][21] I1171N [9][21][56]
  C1156F/D1203N [56] F1174I [56] I1171T [9][21][56]
  C1156F/L1198F [57][58] F1174L [59]  
  C1156Y/D1203N [58] F1245C [59]  
  C1156Y/F1174C [58] G1202del [9][21]  
  C1156Y/F1174I [58] G1202K [52]  
  C1156Y/F1174V [58] G1202L [53]  
  C1156Y/G1269A [58][60] G1202R [9][21][61]  
  C1156Y/I1171T [58] I1171S [9][21]  
  C1156Y/L1196M [58] L1196M [9][21][28]  
  C1156Y/L1198F [58] R1275Q [59]  
  C1156Y/S1256F [58] V1180L [28]  
  D1203N/F1174C [9][21]    
  D1203N/L1196M [60]    
  F1174C/G1202R [23]    
  F1174C/G1269A [58]    
  F1174C/L1196M [58]    
  F1174L/G1202R [23][60]    
  G1202R/G1269A [23][30][57]    
  G1202R/I1171N [23]    
  G1202R/L1196M [24][55][58]    
  G1202R/L1198F [23][58]    
  G1269A/I1171S [48]    
  G1269A/I1171N [58]    
  G1269A/I1171T [58]    
  G1269A/L1196M [23][58]    
  G1269A/N1178H [57]    
  I1171N/C1156Y [23]    
  I1171N/L1198F [23]    
  I1171N/L1256F [23]    
  L1196M/F1174C [58]    
  L1196M/F1174L [58]    
  L1196M/F1174V [58]    
  L1196M/I1171S [58]    
  L1196M/I1179V [58]    
  L1196M/L1198F [58]    
  L1196M/L1198H [58]    
  L1196M/L1256F [58]  
ALK-independent mechanisms of resistance occur when the need for NPM1-ALK is bypassed through the activation of its downstream targets via alternative signalling cascades, so-called bypass tracks (Figure 3 and Table 2) [3][8]. For example, increased signalling through the insulin-like growth factor receptor (IGF-1R) activates the JAK/STAT, MAPK and PI3K/Akt pathways normally stimulated by EML4-ALK or NPM1-ALK, causing crizotinib resistance in NSCLC and ALCL respectively [62][63].
Cancers 13 06003 g005 550
Figure 3. ALK-independent ‘bypass’ mechanisms of resistance to ALK TKIs. The effects of inhibited ALK activity are substituted by the upregulation of alternative signalling cascades that activate the same downstream targets as does aberrantly active ALK. The need for ALK is effectively bypassed. Mutations in the downstream targets of ALK, indicated with a lightning symbol, also bypass the need for ALK.
Table 2. Summary of reported bypass tracks conferring resistance to ALK TKIs.
Protein Alteration
(Upregulation Unless Otherwise Specified)		 ALK TKI Disease
IGF-1R Crizotinib [62][63] NSCLC and ALCL
Epidermal growth factor receptor (EGFR) Crizotinib [8][13][30][64][65]
Ceritinib [30][66]
Alectinib [30][65][67]
Lorlatinib [57][65]		 NSCLC
  Lorlatinib [57] Neuroblastoma
Human epidermal growth factor receptor (HER), including via increased neuregulin 1 ligand Ceritinib and alectinib [68][69] NSCLC
KIT proto-oncogene receptor tyrosine kinase (KIT), including via increased stem cell factor (SCF) ligand Crizotinib [8]
Ceritinib [30]		 NSCLC
MET proto-oncogene receptor tyrosine kinase (MET), including via increased hepatocyte growth factor (HGF) ligand Alectinib [67][70][71][72][73]
Ceritinib and lorlatinib [9][30][49]		 NSCLC
SRC proto-oncogene, non-receptor tyrosine kinase (SRC) Crizotinib [74]
Alectinib [71]		 NSCLC
Discoidin domain receptor tyrosine kinase 2 (DDR2) Alectinib [9] NSCLC
Fibroblast growth factor receptor 2 (FGFR2) Ceritinib [9] NSCLC
ERb-B4 receptor tyrosine kinase 4 (ErbB4) Lorlatinib [57] Neuroblastoma
Interleukin 10 receptor subunit alpha (IL10RA) Crizotinib [75]
Alectinib [75]
Brigatinib [75]
Lorlatinib [75]		 ALCL
Protein tyrosine phosphatase non-receptor tyrosine kinase 1/2 (PTPN1/2) loss Crizotinib [76] ALCL
Alternatively, ALK-independent resistance can be induced due to activation of the pathways downstream of aberrant ALK activity via mutation of genes encoding proteins involved in these pathways (Figure 4). For example, mutations in the MAPK pathway components KRAS [14][31][64][77][78], NRAS [9][30], BRAF [9][30][65][73] and MEK [65][79], as well as reduced DUSP6 (a MAPK phosphatase) [77] and mutations in the RAS negative regulators neurofibromin 1 and 2 (NF1/2) [31][60], cause ALK TKI resistance in NSCLC. Furthermore, lorlatinib and ceritinib resistance has been associated with upregulation of the MAPK pathway in ALCL xenografts [57] and neuroblastoma cell lines [80], respectively. Additionally, PI3KCA mutations cause ALK TKI resistance in NSCLC [9][30][65][79], and lorlatinib resistance of ALCL xenografts has been associated with PI3K/Akt pathway upregulation [57]. Finally, NOTCH1 mutations in NSCLC [31] and ALCL [81], and PIM1 overexpression in neuroblastoma [82], also cause ALK TKI resistance through their effects on the JAK-STAT pathway. In a similar manner, it was shown that activation of signalling via the IL10R bypasses NPM-ALK to activate STAT3 in ALCL mediating resistance to crizotinib, alectinib, brigatinib and lorlatinib [75].
Besides ALK-dependent and independent mechanisms of resistance, there are some additional mechanisms through which ALK TKIs cease to be effective. Some are well studied, such as the CNS relapses that occur if crizotinib and ceritinib are effluxed from the CNS by P-glycoprotein in the blood-brain barrier. These effects can be overcome by using alectinib, brigatinib or lorlatinib as they are not substrates for P-glycoprotein [39]. Other resistance mechanisms are very specific to individual tumour types. For example, NSCLC acquires resistance through epithelial–mesenchymal transition, whereby cells lose their polarity and become more fibroblastic and invasive [9][60][83][84]. NSCLC also acquire resistance through transforming to a small cell lung cancer (SCLC) phenotype, although given that these cells retain their ALK rearrangements, further investigation is required to determine why these transformations mediate resistance [85][86][87][88]. Additionally, neuroblastoma cells driven by MYCN and ALK amplifications can acquire resistance via a multi-step process in which they downregulate MYCN, and instead upregulate and become dependent on BORIS, a DNA binding protein that increases the proliferation and survival of cancer cells, and here causes increased expression of transcription factors that promote the transformation to an ALK TKI-resistant phenotype [89][90]. Further resistance mechanisms are less well studied, such as the generation or loss of different ALK fusions. Indeed, in the case of NSCLC with 3 co-existing rare ALK fusions at diagnosis (COX7A2L-ALK, LINC01210-ALK and ATP13A4-ALK), the generation of an additional SLCO2A1-ALK fusion mediated crizotinib resistance, and the subsequent loss of the ATP13A4-ALK and SLCO2A1-ALK fusions mediated ceritinib resistance [91]. Additionally, increased autophagy in which cells break down obsolete constituents of their own cytoplasm as a way of generating additional energy for tumour growth and proliferation leads to crizotinib resistance in ALCL [92] and NSCLC [93] by allowing the cell to overcome the metabolic stress of the ALK TKI. Indeed, treatment of ALCL cells (both in vitro and in vivo) with crizotinib and chloroquine, which inhibits autophagy, resulted in a greater inhibitory effect than treatment with crizotinib alone, suggesting that there are potential ways of overcoming resistance caused by this mechanism [92].
Another potential cause of resistance to ALK TKIs is p53 disruption. It is already known that TP53 mutation can cause resistance to traditional genotoxic chemotherapeutic agents by preventing apoptosis despite chemotherapy-induced DNA damage [94][95]. However, the resulting genetic instability caused by p53 disruption enables mutations to accumulate over time, and it is these later changes that may drive resistance to targeted agents. This has been shown to be the case in chronic lymphocytic leukaemia [94][95]. Additionally, in neuroblastoma, it has been shown that combination treatment with an ALK TKI and a p53 activator may prevent the resistance seen with ALK TKI monotherapy because the combination stimulates apoptosis rather than reversible growth arrest seen in cells treated with monotherapy [96]. However, p53-mediated resistance to targeted agents has not yet been demonstrated in ALCL. This should be investigated further because p53 is inactivated in some cases of ALCL, occasionally due to TP53 gene mutations [97] but more usually via NPM1-ALK stimulated induction of JNK and MDM2 activity [98]. Additionally, it has been shown that the p53 activator nutlin-3a can induce apoptosis of ALCL and thereby enhance the efficacy of chemotherapy [99].
In summary, due to a large number of possible ALK TKI resistance mechanisms, it is essential that tumours are assessed at the time of resistance to identify the underlying cause, to inform on the next best therapeutic approach towards a cure. For example, the identification of an ALK mutation could dictate which ALK TKI to use next, and the emergence of ALK-independent bypass mechanisms may identify other druggable targets to overcome resistance. Indeed IGF-1R [62], HER [31], HGF [72], SRC [79], MEK [79] and mTOR [100] inhibitors have been shown to overcome ALK TKI resistance caused by activation of these bypass pathways. Therefore, these could be considered as future treatments in these cases. It is also imperative that further potential resistance mechanisms continue to be identified in the laboratory as for many patients, the mechanisms cannot be explained by known pathways. In evidence, a large study of NSCLC patients resistant to ALK TKIs found that only 33–44% of the resistance phenotype could be explained by currently known resistance mechanisms [30]. This is even more important for ALCL, as well as neuroblastoma, because the majority of known ALK TKI resistance mechanisms have been studied in NSCLC and may differ substantially between diseases due to differing underlying biology and activities specific to the type of aberrant ALK expression observed, including overexpression of full-length ALK, compared to a fusion protein.
Additionally, the schedule of ALK TKI delivery and the combination of drugs with which it is administered may also impact resistance mechanisms. For example, resistance may be delayed or prevented when combination therapies are given upfront rather than as sequential monotherapies; when therapy is given in a metronomic manner; or when treatments are cycled before resistance has developed rather than changing treatment once resistance has already developed. In particular, alternating ALK TKIs based on the additional proteins that they target other than ALK may be useful in reducing the selective pressure leading to specific ALK mutations and bypass resistance tracks. For example, crizotinib (also an MET and ROS1 inhibitor [22]) could be cycled with alectinib (also an RET, LTK and GAK inhibitor [22]). Furthermore, it has been demonstrated in NSCLC that MET-driven ALK TKI bypass resistance is present at lower levels in patients treated with a less selective ALK TKI [101]. This requires investigation specific to ALCL but suggests that the development of drugs with potent ALK inhibition, but not necessarily more ALK specificity, is required.

3. Mechanisms of Resistance to Brentuximab Vedotin

Resistance to BV develops relatively frequently, with around half of patients with relapsed/refractory ALCL treated with BV either progressing on therapy or requiring additional treatments [102]. The most obvious mechanism of resistance is a reduction in CD30 protein expression, the target of BV activity. This has been observed in at least one case of adult ALK-negative ALCL [103] and in epithelioid inflammatory myofibroblastic sarcoma patient-derived xenografts (PDXs) [104]. It is unclear whether these reductions in CD30 were due to downregulation of the CD30 target, increased turnover of CD30, CD30 internalisation, or the selective outgrowth of sub-clones with lower levels of CD30 expression [104]. However, CD30 target reduction does not account for all BV resistance because CD30 expression is maintained in some BV-resistant Hodgkin lymphoma and ALCL [105]. A second potential resistance mechanism is upregulation of ABC transporters, which has been demonstrated in BV-resistant Hodgkin lymphoma cell lines and patient samples [105][106][107], and epithelioid inflammatory myofibroblastic sarcoma PDXs [104]. However, this also cannot account for all BV resistance because Hodgkin lymphoma cells treated with BV and an MDR-1 inhibitor eventually stop responding to this combination [107].
In summary, further work is required to fully elucidate how to use BV in paediatric ALK-positive ALCL. In order to explore whether BV might allow traditional chemotherapy to be reduced, a better understanding of BV resistance mechanisms is required. This will help to establish whether it can be used as a monotherapy, with factors put in place to prevent the acquisition of resistance, or whether it should only ever be used alongside other agents.

4. Mechanisms of Resistance to Immune Checkpoint Inhibitors

Resistance to anti-PD-L1 immune checkpoint inhibitors will eventually occur in the majority of patients, although there are differences in rates between tumour types. This can be a consequence of PD-L1 upregulation [108][109][110], which can occur due to increased JAK-STAT signalling, caused by: loss of the tumour suppressor FBP1 [109][111], mutations in JAK1/2 [112], or stimulation of tumour cells’ interferon-gamma receptor 2 by interferon-gamma released from activated CD8+ T cells in the tumour microenvironment [113][114]. PD-L1 upregulation can also occur when loss of the tumour suppressor PTEN results in increased PI3K/Akt signalling [109][110].
Alternatively, resistance to anti-PD-L1 immune checkpoint inhibitors can occur as a result of a skew in the distribution of immune cells in the tumour microenvironment towards an immunosuppressive one, compensating for the effects of loss of PD-L1 signalling. This skew can be caused by a low overall T cell abundance [114], an increased ratio of regulatory T cells to effector T cells [115], dysfunctional CD8+ T lymphocytes [116][117], increased myeloid-derived suppressor cells (MDSCs) [118] and/or increased PD-L1 positive M2 macrophages [118][119]. These changes are mediated in a variety of ways (Table 3), which might be therapeutically targetable. For example, a clinical trial (NCT03048500) is investigating whether metformin used alongside nivolumab in NSCLC can overcome the nivolumab resistance caused by the detrimental effects of hypoxia on CD8+ lymphocytes [117][120].
Table 3. A skew towards immunosuppression in the tumour microenvironment can drive resistance to immune checkpoint inhibitors.
Event Impact on the Tumour Microenvironment
Increased AXL receptor tyrosine kinase (AXL) expression Increases regulatory T cells, MDSCs and M2 macrophages [118]
Increased Wnt signalling Decreases tumour infiltrating lymphocytes [118]
Loss of Phosphatase and tensin homolog (PTEN) Induces vascular endothelial growth factor (VEGF) production and reduces T cell infiltration [109][118]
Loss of functional beta 2 microglobulin Dysfunctional CD8+ T cells [108][121]
Hypoxia Dysfunctional CD8+ T cells [117][120]
Upregulation of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) Dysfunctional T helper 1 (Th1) cells and reduced cytokine expression [122][123]
Reduced expression of absent in melanoma 2 (AIM2) Decreases inflammation [114]
Reduced expression of poliovirus receptor-related immunoglobulin domain containing protein (PVRIG) Dysfunctional CD8+ T cells [114]
Increased expression of mannosidase alpha class 2A member 1 (MAN2A1) Altered Th1/T-helper 2 (Th2) axis towards Th2 expression [114]
 

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