Repertoire for the Treatment of Malignant Melanoma: Comparison
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Immune checkpoint inhibitors (ICIs) have been used for the treatment of various types of cancers, including malignant melanoma. Mechanistic exploration of tumor immune responses is essential to improve the therapeutic efficacy of ICIs. Since tumor immune responses are based on antigen-specific immune responses, investigators have focused on T cell receptors (TCRs) and have analyzed changes in the TCR repertoire. The proliferation of T cell clones against tumor antigens is detected in patients who respond to treatment with ICIs. The proliferation of these T cell clones is observed within tumors as well as in the peripheral blood. Clonal proliferation has been detected not only in CD8-positive T cells but also in CD4-positive T cells, resident memory T cells, and B cells. Moreover, changes in the repertoire at an early stage of treatment seem to be useful for predicting the therapeutic efficacy of ICIs. Further analyses of the repertoire of immune cells are desirable to improve and predict the therapeutic efficacy of ICIs. 

  • melanoma
  • immune checkpoint inhibitor
  • repertoire

1. Introduction

Immune checkpoint inhibitors (ICIs) are currently used for the treatment of various types of cancers, including malignant melanoma [1]. However, only approximately 30–50% of melanoma patients respond to treatment with ICIs; thus, their therapeutic efficacy needs to be improved [2][3].,3]. The analysis of “tumor antigen-specific immune responses”, which represent an important part of immune responses to tumors, can aid in improving the therapeutic efficacy of ICIs [4][5].[4,5 ]. Therefore, changes in the repertoires of immune cells that recognize tumor antigens have been analyzed [6]. Multiple studies have reported that the

ICI-induced restoration of exhausted antitumor immune responses allows for the clonal proliferation of immune cells and produces therapeutic benefits [7][8][9]. ,8,9].

2.Treatment and Repertoires

2.1. Changes in the Repertoire with ICIs

PD-1 blockade restores T cell functions primarily at the effector phase. Therefore, PD-1 blockade rescues exhausted CD8-positive T cells and restores their cytotoxic capacity, thereby facilitating the destruction of tumor cells [10][50]. Anti-PD-1 antibodies prevent PD-1 from binding to PD-L1 on APCs and interfering with the differentiation and functioning of Treg cells because PD-1 plays a role in the development of Treg cells [11][51]. However, the PD-1 expression pattern encompasses a broad range of immune cells, including T cells, B cells, natural killer cells, dendritic cells, and bone marrow cells. Its ligands, PD-L1 (programmed death-ligand 1) and PD-L2, are also expressed in various hematopoietic and nonhematopoietic cells as well as cancer cells [12][13].[52,53]. Therefore, anti-PD-1 therapy can affect various types of cells and pathways. Recent analyses have mainly focused on CD8-positive T cells, which play a major role in tumor immune responses. After anti-PD-1 therapy, most of the abundant TIL clones were found among T cell clones in peripheral blood, regardless of the clinical response [9]. T cell clones expressing TCRs that recognize tumor antigens proliferate in anti-PD1 antibody responders [7][14].,54]. Moreover, an analysis in patients who underwent neoadjuvant anti-PD-1 antibody therapy revealed a post-treatment increase in the number of CD8-positive T cells reactive with gp100, a melanoma-specific antigen [15].[55]. These findings suggest that the ICI-induced restoration of exhausted antitumor immune responses is followed by the clonal proliferation of immune cells, yielding therapeutic benefits. Meanwhile, blockade of CTLA-4, another immune checkpoint protein, decreases the T cell priming threshold and allows for the proliferation of more effector T cells [16].[56]. Anti-CTLA-4 antibodies also allow for the proliferation of memory T cell clones [17][57]. Moreover, Treg cells in the tumor microenvironment are depleted as they express CTLA-4 [18].[58]. Depletion of Treg cells improves intratumoral IL-2 levels, facilitates survival of CD8-positive T cells, and expands the TCR repertoire [19].[59]. In other words, anti-CTLA-4 antibodies inhibit Treg cells, reverse inhibit CD8-positive T cells, and expand the TCR repertoire in a nonspecific manner[60]. [20]. In addition, anti-CTLA-4 antibodies accelerate the turnover of T cell repertoire and increase TCR diversity [21][22][23].[61,62,63]. Anti-CTLA-4 antibodies broaden the T cell repertoire, whereas anti-PD1 antibodies promote the proliferation of a limited number of clones, skewing the T cell repertoire (Figure 1).

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Figure 1. Repertoire changes with immune checkpoint inhibitors.
A previous study showed tumor antigenic changes after PD-1 blockade [24][64]. Thus, a dynamic clonal change in the TIL could be induced by antigenic alteration of tumor cells during treatment [24][64], whereas the clone of TIL expanded after PD-1 blockade responded to tumor cell line before PD-1 blockade [25][65]. Therefore, the authors reported that dynamic tumor-specific clonal changes after PD-1 blockade are caused by PD-1 blockade but not antigenic alteration of tumor cells [25][65]. T cells use TCRs to recognize antigen peptides presented by MHC on antigen-presenting cells. CD28 receives stimulus from CD80/86, which leads to T cell activation. CTLA-4 competes with CD28 and inhibits T cell activation. Therefore, inhibition of CTLA-4 results in nonspecific proliferation of T cell clones and expansion of the TCR repertoire. On the other hand, T cells use TCRs to recognize antigen peptides on tumor cells for eliciting antitumor immune responses, and tumor PD-L1 binding to PD-1 on T cells inhibits the antitumor immune responses. PD-1 inhibition promotes the proliferation of specific T cell clones, leading to alteration of the TCR repertoire.

2.2. Changes in the Repertoire with BRAF/MEK Inhibition

MEK inhibitors can impair T cell activation, because T cell activation mediated by TCRs and their co-stimulatory molecules is dependent on mitogen-activated protein kinase (MAPK) and the PI3K-AKT signaling cascade [26][66]. In fact, pharmacological in vitro inhibition of MEK had adverse effects on T cell activation [27][67]. In contrast, the results of an in vivo analysis were twofold: MEK inhibition had no adverse effects on T cell effector function and showed favorable outcomes in combination with immune checkpoint inhibition [28][68]. MEK inhibition was associated with increased tumor-infiltrating CD8-positive T cells, increased IFN-γ gene expression signatures, and decreased abundance of tumor-associated macrophages and Treg cells. Furthermore, MEK inhibition protected effector T cells from activation-induced cell death due to chronic TCR stimulation [29][69]. In addition, an analysis in melanoma patients showed that BRAF/MEK inhibition upregulated the levels of T-bet and TCF7 and expanded T cell repertoire in tumors [30][34]. Another study showed that higher intratumoral T cell clonality was associated with better responses to BRAF inhibitor treatment for melanoma [31][70]. Based on these results, efficacy analyses of ICIs combined with BRAF/MEK inhibitors are desired in clinical trials.

2.3. Changes in the Repertoire with Adoptive Cell Transfer of TIL Therapy

Adoptive cell transfer (ACT) of TIL is used for the treatment of advanced melanoma. ACT of TIL has shown significant clinical benefit [71]. However, ACT of TIL could not work enough in patients previously treated with PD-1 or MAPK inhibition [68]. Response to ACT correlates with the recognition of tumor neo-antigens [72,73]. Anti-PD-1 naïve patients were received TIL reactive with more neo-antigens compared with anti-PD-1 experienced patients [74]. Treatment products administered to anti-PD-1 naïve patients were more likely to contain T cells reactive against neoantigens than treatment products for anti-PD-1 experienced patients [74].

2.4. Changes in the Repertoire with IL-12 Therapy

IL-12, an inflammatory cytokine, induces the proliferation and activation of natural killer (NK) cells and cytotoxic T cells and enhances effector functions [32][33][75,76]. Additionally, it is an important link between innate and acquired immune systems, because APC-producing IL-12 stimulates the release of IFN-γ from T cells and NK cells [34][77]. It is also involved in Th1 induction and promotes IFN-γ production [35][78]. Thus, IL-12 plays a role in antitumor immunity, and T cells are important for IL-12-mediated tumor suppression [36][79]. Intratumoral plasmid IL-12 electroporation therapy was tested in a phase II trial in melanoma patients [37][80]. Following the treatment, intratumoral T cells proliferated clonally, which led to a skewed TCR repertoire.

2.5. Treatment Correlations and Repertoires

CTLA-4 is expressed mainly on CD4-positive T cells after TCR-mediated activation and interferes with CD28 co-stimulatory signaling induced by APCs to inhibit TCR-induced activation and proliferation [3[8]1]. Therefore, CTLA-4 inhibition induces the activation and proliferation of antitumor T cells via increased CD28 signaling. PD-1 inhibits the effector function of antigen-specific T cells upon binding to ligands [39][82]. PD-1 inhibitors directly regulate the functions of various types of PD-1-expressing immune cells [40][83]. Immunotherapy with anti-PD-1 antibodies is widely used for the treatment of metastatic solid tumors, with a response rate of 20–55% [3]. Biomarkers to predict which patients are likely to respond to anti-PD-1 antibody therapy are needed. Because highly variable CDR3 of the TCR chain is unique to individual T cell clones, CDR3 can be used to monitor the dynamics of T cell repertoire responses to ICIs [[841]]. A recent study showed that the TCR clonality or diversity of T cells in the blood increases 3 weeks after the initiation of treatment with anti-PD-1 antibodies [7]. Clonal proliferation of TCRs in the blood also occurred only in responders 3 weeks after the initiation of combination treatment with anti-PD-1 and anti-CTLA-4 antibodies. Thus, with this approach, minimally invasive liquid biopsies may be used in the early stages of treatment to predict patients’ treatment response. The anti-PD-1 antibody treatment seems to be more effective in melanoma patients when the pretreatment TCR repertoire of TILs is larger in metastatic tumors [42][85]. An analysis of melanoma in The Cancer Genome Atlas reveals that a larger TCR repertoire of TILs is associated with longer overall survival even without anti-PD-1 antibody treatment. Furthermore, TCR repertoires in the peripheral blood of melanoma patients were examined to determine whether the TCR diversity predicted the clinical prognosis of ICI treatment [43][20]. Higher TCR repertoire diversity in the blood was associated with longer progression free survival, and low repertoire diversity was associated with poor prognosis. The diversity in patients who experienced late recurrence and long-term survival was significantly higher than that in rapid progressors. The TCR repertoire diversity in tumors may have a potential prognostic value. Liquid biopsies were performed before treatment to predict responses to ICIs [44][86]. In the PCR analysis of pretreatment peripheral blood mononuclear cells (PBMCs), the diversity evenness of the TCRs repertoire score was correlated with the therapeutic efficacy of ICIs. Furthermore, the pretreatment level of TCR repertoire restrictions in CD4-positive T cells in peripheral blood had a potential prognostic value for clinical response to CTLA4 inhibition [43][20]. In addition, T cells release their DNA into the blood when cell death occurs. The released cell-free DNA in the blood was sequenced for analyzing CDR3 of T cells [23][63], which suggested that the clonal proliferation of T cell repertoire in the blood within 3 weeks of starting ICI treatment predicts the therapeutic efficacy.

2.6. Immune-Related Adverse Events and Repertoires

Anti-CTLA-4 and anti-PD-1 therapies can prolong survival in melanoma patients; however, these therapies can also induce organ-specific toxicities, called immune-related adverse events (IrAEs), which make it impossible to continue ICIs in a considerable number of patients [7][45],87]. It is likely that T cell clonal analysis is useful for the early diagnosis of IrAEs. The number of T cell clones that newly underwent proliferation was higher in patients with severe IrAEs after CTLA-4 blockade [46][88]. Furthermore, newly expanded clones were found among CD8-positive T cells, but not CD4-positive T cells, in patients with IrAEs [47][89]. In addition, severe repertoire restrictions were found in CD4-positive T cells in a study using samples of severe colitis [48][22]. CD4-positive and CD8-positive T cells may be diversely involved in various IrAEs; further studies are necessary for clarifying this point.

2.7. Repertoire Analysis and Vaccines

Peptides recognized by TCRs are used as vaccines to enhance antitumor immune responses [4[9]0]. Specifically, tumor biopsy specimens and nonmalignant tissue samples (usually PBMCs) are collected from patients and subjected to whole exome sequencing for comparison between tumor DNA and germline DNA to identify tumor-specific somatic mutations. A computational approach is used to predict MHC class I-binding epitopes, and peptides predicted to have moderate-to-high MHC-binding affinities are likely to induce CD8-positive T cell responses [50][91]. MHC class II-binding peptides are often more difficult to predict. The peptide-binding groove of MHC class I has closed ends to define the arrangement of a peptide epitope composed of 8–11 amino acid residues for presentation to CD8-positive T cells. In contrast, the peptide-binding groove of MHC class II has open ends and can bind to a peptide that is longer and more variable in length. Recently, new methods have been developed for the prediction of MHC class II-binding peptides [51][52][53][92,93,94], and they are expected to promote the development of MHC class II-binding peptides to elicit tumor-specific responses of CD4-positive T cells.

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