The use of IHC, cytogenetics, and molecular evaluations have had a significant impact on the diagnostic accuracy and subtype assignment of TCL[29, 30]. However, there is still no universally accepted standard treatment for TCL patients despite the concentrated efforts to facilitate this over the last few decades, resulting in our deeper understanding of these diseases[31, 32]. New targeted therapies for TCL are constantly emerging because patients with TCL exhibit higher rate of failure and relapse in response to first-line treatments as compared to that seen in B cell lymphomas. A variety of target-specific treatments are undergoing clinical trials and are expected to help improve prognosis in patients with TCL. These interventions were designed based on the following mechanisms[33, 34]: (1) Epigenetic regulation, mainly consisting of histone deacetylase inhibitors (HDACi), like Vorinostat, Belinostat, Romidepsin, Panobinostat, Chidamide, Quisinostat, and AR-42[35]; (2) Antibody dependent cell-mediated cytotoxicity (ADCC), including technologies like Brentuximab vedotin (targeted CD30), Daratumumab (targeted CD38), Alemtuzumab (targeted CD52), IPH4102[36] (targeted KIR3DL2), TTI-621[37] (targeted CD47), and AFM13[38] (targeted CD30/CD16A); (3) Cytotoxic reactions, involving chimeric antigen receptor T or NK (CAR-T/CAR-NK) cells with anti-CD7, anti-CD4, anti-CD5 or anti-TCR capabilities; (4) Signaling pathway blockers, including anaplastic lymphoma kinase (ALK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and microRNA (miR)-155 inhibitors[39]; (5) Other agents, such as E7777[40] (an immunotoxin targeting the interleukin (IL)-2 receptor), Alisertib[41] (an inhibitor of Aurora A kinase (AAK)), and various antibiotics from Staphylococcus aureus[42] amongst others. However, to date, none of these technologies have produced a satisfactory outcome in patients with TCL, suggesting that further interventions are needed.
Recently, insights into tumor lactic acid metabolism, especially the transporters on the cell membrane, have generated meaningful breakthroughs about MCTs, resulting in several ongoing studies evaluating the inhibition of the MCTs or the mechanisms underlying MCT function and their roles in oncogenesis and progression. Lactate is the major substrate for energy production in cancer cells and acts as a signaling molecule in these cells. It has also been shown to play important roles in tumor progression, including inducing tumor angiogenesis, inhibiting histone deacetylases, stimulating amino acid metabolism, activating lactate receptor GPR81, and inducing tumor immune tolerance[43]. Therefore, MCTs, which control the transmembrane flux of lactate, have become targets of rigorous evaluation in various types of cancers. Doherty[44] et al. showed that disrupting the function of MCT1 can lead to an accumulation of intracellular lactate and tumor cell death, while Baek et al. reported that MCT4 depletion induces cell death, which is characterized by elevated reactive oxygen species and metabolic crisis[45]. Pértega-Gomes et al. believed that MCT2 should be explored as a tumor marker[46] and several studies have evaluated the expression levels of various MCTs in different cancers and shown that they share a similar pattern of dysregulation in various cancers. However, their expression in TCLs is largely undefined. Our study evaluated MCT expression in TCL, and revealed that MCT1 and MCT4 exhibit high expression levels in tissue samples from patients with TCL. These results are consistent with the open-access data for SLC16A1 and SLC16A3 reported in the CCLE. To the best of our knowledge, MCT1 has also been found to be highly expressed in lung cancer[47], breast cancer[47, 48], brain cancer[49], cervix cancer[15], skin cancer[16], soft tissue cancer[50], and B cell lymphomas[24]. However, Noble et al. reported that little to no MCT4 protein was present in most patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL)[24], and this contradicts with our results in patients with TCL. AZD3965, a selective inhibitor of MCT1, is under phase I clinical trials for use in adult solid tumors and two types of B-cell lymphoma, DLBCL and BL[19]. Likewise, as a subgroup of the non-Hodgkin lymphomas, TCLs are likely to respond to MCT1 inhibition and thus benefit from these new inhibitors, even though the incidence of TCL is much lower. That said there is still a long way to go in linking MCT1 targeted treatment with improved outcomes in patients with TCL, including their evaluation in animal models. But before that, we need to establish whether increased MCT1 expression affects the prognosis of patients with TCL.
Our study may provide a preliminary answer to this question. Survival analyses indicated that TCL patients with high levels of MCT1 expression were more likely to have shorter OS and PFS, while those with high MCT4 expression did not exhibit any significant differences in these parameters. Similarly, our evaluation of the prognostic significance of MCT1 and MCT4 demonstrated similar results to those of a previous study in head and neck cancer samples[51]. However, this was not the case with several other types of cancers, as high levels of MCT4 have been linked to poor prognosis in patients with prostate cancer[46], pancreatic cancer[45], lung adenocarcinoma[52], and non-small cell lung cancer (NSCLC)[53]. Moreover, we found that high levels of MCT1 was more common in female patients, advanced stages of disease, in tissues with increased serum LDH and a Ki-67 index of more than 50% than their counterparts. These characteristics, except for sex, are also already considered risk factors for patients with NHL[54, 55]. Interestingly, we found that female patients with TCL presented with higher MCT1 but lower MCT4 expression than their male counterparts, but this needs to be verified using a larger sample size in the future. We also completed a series of comparisons using a risk-based stratification method which revealed that patients in the intermediate-and high-risk groups also exhibited higher MCT1 protein expression levels than those in the low-risk group. Thus we speculate that high MCT1 expression is related to poor prognosis in patients with TCL, although the mechanism of this remains unknown.
Notably, the differences in MCT1 expression between subgroups were generally more apparent than the differences in MCT4 expression. Although this does not mean MCT1 is more valuable than MCT4 in TCL prognosis, we can conclude that high expression levels of MCT1 can be considered a considerable risk factor in these patients. We did not observe any significant differences in MCT1 or MCT4 expression between TCL subtypes (confined to PTCL-NOS, AITL, and ENKTL), and further studies should evaluate this in more detail for some of the rarer subtypes. Currently, out of all the lymphomas, only DLBCL and BL are currently implicated in any of the clinical trials for selective inhibitor AZD3965, which inhibits MCT1. Previous studies have not compared MCT1 expression levels in these two NHL subtypes nor explicitly proposed which is more amenable to AZD3965[24, 25]. In the case of DLBCL, two related studies have both revealed that MCT1 expression is increased in patient tumor samples and that this increased expression is associated with poor prognosis. However, evaluation of MCT4 expression revealed a distinct difference in the positivity rates for these two studies, reporting 27% and 65.6% positivity respectively. Afonso et al. concluded that MCT1 might serve as a target for treating patients with NHL (or DLBCL) with high MCT1/low MCT4 expression[25]. This means that our data, which showed that TCL samples can present with increased expression of both MCT1 and MCT4, does not meet this criterion. However, this literature also suggests that these results were obtained in vitro and need to be confirmed in additional studies designed to evaluate novel therapeutic strategies. Our data suggests that TCL may be amenable to treatment with MCT1 selective inhibitors, but this requires preclinical validation both in vitro and in vivo.
In summary, we analyzed the expression of MCT1 and MCT4 in TCL using IHC and explored their prognostic value in relation to specific clinical parameters. We found that both MCT1 and MCT4 were highly expressed in the pathological tissues of TCL patients, and that high MCT1 expression may be associated with poor OS and PFS in these patients. Our results also indicate that patients with TCL in the high-and intermediate-risk groups exhibit higher MCT1 expression levels than those in the low-risk group. In addition, high MCT1 expression is also more common in female patients and those with advanced stage disease, increased serum LDH levels and Ki-67 at ≥ 50%. Taken together this data suggests that MCT1 inhibition may be a valid choice for treating TCL, but more data from larger populations and preclinical studies are required to confirm this hypothesis.