September 28, 2022

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A decade of checkpoint blockade immunotherapy for melanoma

A decade of checkpoint blockade immunotherapy for melanoma


A decade of checkpoint blockade immunotherapy for melanoma.


Melanoma is the most aggressive and deadly form of skin cancer.

Several historical observations suggest that melanoma is an immunoreactive tumor, often associated with UV exposure and elevated tumor mutational burden ( TMB ), which contribute to improved immunogenicity.

Melanoma often has reactive lymphocytic infiltration, and the degree of peritumoral lymphocyte infiltration is associated with better prognosis, and classification of melanoma ( active, inactive, and absent ) based on the distribution of tumor-infiltrating lymphocytes ( TILs ) is still used today.


It has been ten years since the immune checkpoint inhibitor ipilimumab was approved for advanced melanoma in 2011, making it the first treatment to prolong survival in melanoma.

Then, in 2014, another key T-cell immune checkpoint PD-1 inhibitor, pembrolizumab and nivolumab, was approved for the treatment of metastatic melanoma.


Although the clinical success of immune checkpoint blockade ( ICB ) in melanoma has demonstrated the efficacy of reactivating the immune system to treat the disease, however, even in optimal regimens in combination with ICB, long-term outcomes are still not achieved in approximately half of patients benefit.

This suggests the need for better response-predicting biomarkers and new rational targets to overcome immune resistance with more effective combination therapies.

It is time to review the lessons learned in modulating the immune system to treat cancer to further expand new approaches to the efficacy of current and emerging immunotherapies.




Melanoma-specific T cells

Melanoma tumors are enriched in TILs specific for melanoma-associated antigens, suggesting that anti-melanoma T cells can undergo priming, expansion, and then re-recruitment to tumors.

Endogenous T cell responses in melanoma have been exploited for a variety of treatments including

(1) recognition of cognate antigens, which are then used in vaccine development;

(2) tumor-specific T cells for adoptive cell therapy ( ACT ) Amplification and/or engineering.


A decade of checkpoint blockade immunotherapy for melanoma



Research into melanoma TILs was facilitated with the discovery of IL-2 in 1977, enabling T cells to be expanded in vitro to characterize their properties.

A variety of T cells were identified that recognize melanoma-associated tumor antigens, including:

1) Carcinoembryonic antigens: ( eg Mage-A1, NY-ESO-1 ) they are methylated and silenced in adult tissues, But tumors usually have abnormal DNA methylation patterns, resulting in demethylation and ectopic expression;

2) Melanocyte differentiation antigens: such as MART-1, gp100, tyrosinase, which are involved in the normal differentiation of melanocytes play a role in the tumor and thus shared between tumors and melanocytes.

3) Overexpressed antigens: such as PRAME;

4) Neoantigens: Neoantigens originate from tumor-specific somatic mutations that do not exist in the normal human genome and are only expressed in cancer cells.

5) Other sources: Immunogenic epitopes can also arise from mutations associated with gene fusions, aberrant mRNA splicing leading to intron retention, or aberrant translation leading to cryptic antigens.


Collectively, the presence of melanoma-specific TILs suggests that in many cases (1) these cells are not sufficient in number or function to completely eradicate tumors, and (2) they can be enhanced to achieve the desired level of complete tumor eradication in vivo quantity.

To achieve this goal, ACT using ex vivo-expanded TILs was shown to contribute to tumor regression, especially in melanoma.




B cell responses in melanoma

Melanoma antigens also induce B cell responses, further supporting the immunogenicity of the disease.

Autoantibodies against melanoma-associated antigens have been reported to be produced in melanoma patients and have been associated with improved prognosis in some cases.

However, whether anti-melanoma antibody responses play a causal role in tumor protection remains to be fully elucidated.


Mature B cells are more frequently present in melanoma lesions compared to normal skin, clustered with T cells and dendritic cells ( DCs ) to form tertiary lymphoid structures ( TLSs ).

Key mediators of TLS formation, including early ( CXCL13 ), mid-stage ( lymphotoxin beta receptors ) and late-stage lymphangiogenic factors ( CCL21, LIGHT ), can be overexpressed in metastatic melanoma.

Chronic immunogenic stimulation elicited by melanoma-associated antigens may trigger TLS support signals to recruit and expand tumor-specific B cells.

B cells and their antibody products can be highly heterogeneous, with features ranging from pro-inflammatory ( IgG1+ ) to immunosuppressive ( eg, CD1d+IL-10+PD-L1+, IgA+, IgG2+, or IgG4+ ).

This heterogeneity may explain the apparently contradictory findings of independent studies between B-cell infiltration and negative prognosis in melanoma patients. These differences may also be explained by the diversity of immune signaling in the microenvironment and its impact on the polarization of intratumoral B cells towards pro- or anti-inflammatory directions.


TLS is highly dynamic and can also attract immunosuppressive cells, such as regulatory T cells ( Tregs ), immature tolerogenic DCs and/or myeloid-derived suppressor cells ( MDSCs ), in response to excessive inflammation.

Precise measurement of the immunostimulatory and immunosuppressive potential of tumor-associated TLS and the likelihood of predicting its fate based on composition and inflammatory signaling will provide potentially valuable biomarkers of immunotherapy response.

Indeed, despite the many unknowns of TLS and intratumoral B-cell biology, recent reports have linked these factors to improved patient response to ICB.



Mechanisms of immunosuppression in melanoma

Although melanoma is immunogenic, metastatic melanoma does not usually resolve spontaneously.

Strong immune selection pressure on melanoma immunogenicity induces tumor adaptation and suppresses antitumor immunity.

Furthermore, local inflammation activates homeostatic immune feedbacks that contribute to this adaptive resistance.

For example, intratumoral CD8+ T cells induce PD-L1 expression and intratumoral Treg accumulation on tumor cells by producing CCL22 and IFN-γ , respectively .


Melanoma can also attract immunosuppressive cells directly. Especially through MHC-II expression, melanoma cells have a unique ability to interact with and attract a subset of immunosuppressive CD4+ T cells.

Treg was increased in peripheral blood ( PB ), lymph nodes and tumor microenvironment ( TME ) of melanoma patients and was found to inhibit TIL function.

Recent single-cell omics studies have demonstrated that melanoma-infiltrating Tregs are highly clonal and can recognize tumor cells through TCR:pMHC II interactions, suggesting that melanoma cells can directly activate and expand Tregs to control local immunosuppression.

Notably, clonal expansion of tumor-specific Tregs was found to correlate with neoantigen load, which in turn correlated with tumor expression of MHC-II, further pointing to a mechanism by which melanoma controls Treg expansion through MHC-II expression. , depending on its immunogenicity.


Furthermore, in melanoma patients, a preference for Th2-polarized CD4+ T cells and related cytokines has been reported, and Th2 immune bias is an indicator of chronic inflammatory responses.

Human melanoma cells overexpressing VEGF and galectin-9 support this Th2 bias through M2 macrophage differentiation, thereby promoting tumor-promoting inflammation.


DCs play a key role in controlling local inflammation, T-cell recruitment, and melanoma activation. Multiple studies have shown that melanoma cells and local inflammation negatively affect intratumoral DC abundance and co-stimulatory capacity through multiple mechanisms, thereby limiting the generation of effective T cell responses.




The latest progress of ICB in the treatment of melanoma

The first immune checkpoint inhibitor used in the treatment of melanoma was ipilimumab, which targets CTLA – 4 , and was first indicated for metastatic melanoma in 2011 . Then in 2014 , the PD-1 inhibitors pembrolizumab and nivolumab were approved for metastatic melanoma.

Considering the distinct and potentially complementary effects of CTLA-4 and PD-1 blockade, subsequent trials of these therapies in combination demonstrated better long-term efficacy in metastatic melanoma than either agent alone, 49% of patients were still alive after 6.5 years, albeit at the cost of greater toxicity.

Alternative and / or dosing regimens of anti- PD-1 + anti- CTLA-4 are currently being investigated to reduce toxicity.


The discovery of immune co-inhibitory receptors in depleted T cells has stimulated further development of antibody therapies targeting novel immune checkpoint molecules.

The most promising novel ICB target is LAG-3, a surface inhibitory receptor structurally similar to CD4 that competes with MHC-II and other ligands such as galectin-3 for binding.

Similar to CTLA-4, LAG-3 is also constitutively overexpressed on Treg, promoting its suppressive function. Although LAG-3 inhibitors as monotherapy have moderate antitumor efficacy, the combination anti-LAG-3 + anti-PD-1 demonstrated significantly enhanced therapeutic activity in several mouse tumor models, including melanoma.


Currently, the leading anti-LAG3 antibody is relatlimab. In March, the FDA approved a fixed-dose combination of relatlimab in combination with nivolumab for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

Results of the clinical trial showed that relatlimab + nivolumab was associated with a higher progression-free survival ( PFS ) rate than nivolumab monotherapy, at 10.1 months in the relatlimab + nivolumab arm compared to 4.6 months in the nivolumab monotherapy arm.


Other advances in ICB in melanoma have come from its studies in early-stage disease, where ICB is given after surgical resection ( adjuvant therapy ) or before surgical resection ( neoadjuvant therapy ).

ipilimumab, the first ICB therapy to show durable survival benefit in melanoma in adjuvant setting, followed by PD-1 blockade with nivolumab or pembrolizumab showed improved outcomes in high-risk stage III patients compared to placebo or even ipilimumab Relapse-Free Survival ( RFS ).

Given the improved toxicity profile compared to ipilimumab, PD-1 blockade has become the standard of care for adjuvant therapy. Recently, adjuvant pembrolizumab received FDA approval for stage II/C melanoma.


Neoadjuvant ICB has also progressed, with five studies completed so far in melanoma. Neoadjuvant ipilimumab + nivolumab or PD-1 blockade alone showed pathological complete response ( pCR ) rates of 33-57% and 19-25%, respectively.

In addition, an alternative combination regimen is also being studied, with the neoadjuvant nivolumab + relatlimab showing an impressive pCR rate ( 59% ).




Targeting melanoma metabolism to overcome immunotherapy resistance

Despite the success of ICB , the efficacy of these therapies, even in combination, has reached an upper limit, and new drugs are urgently needed.

Tumor cells are typically adapted to aerobic glycolysis, and in the TME , cancer cells have a metabolic advantage over normal immune cells, thereby facilitating tumor progression and immune evasion.

At present, tumor metabolism is becoming a key target and may be used in combination immunotherapy for targeted therapy.


Metabolic competition is particularly relevant in melanoma, where elevated glycolysis in human melanoma is inversely associated with T cell infiltration and activation and response to ACT or ICB.

Progressive melanoma can acquire a hypermetabolic phenotype that maintains oxidative metabolism.

To counteract this hypermetabolic phenotype and enhance immunotherapy, antidiabetic biguanides are being studied in melanoma.

Patients receiving metformin had a reduced incidence of new brain metastases and a favorable prognosis.


A decade of checkpoint blockade immunotherapy for melanoma



Furthermore, reduced oxygen tension in the hyperoxidative tumor microenvironment promotes reactivation of T-cell exhaustion and T-cell PD-1 resistance.

In contrast, tumor glycolysis and glucose deprivation in the microenvironment have a preferential effect on CTLA-4 blockers.

The preferential resistance of oxidative and glycolytic tumor metabolism to anti-PD-1 and anti-CTLA-4 inhibitors, respectively, can be explained, at least in part, by the different cellular localization of these immunotherapeutic direct targets.

PD-1 blockade acts primarily to reinvigorate dysfunctional PD-1+ T cells, whereas CTLA-4 blockade has an effect against Tregs, which are more stable in glucose-starved environments.

Recent studies have shown that targeting lactate or fatty acid metabolism in Treg enhances the response to ICB in mouse melanoma models.





Immune checkpoint inhibitors have been approved for the treatment of advanced melanoma for a decade.

Over the past decade, with our further understanding of the human melanoma immune microenvironment, we have made great achievements in exploring new drugs and new therapies based on immune checkpoint inhibitors.


However, as more and more drugs become available, we need to clarify the mechanism of combination immunotherapy to guide rational combination. We need to focus on: robust biomarkers, resistance mechanisms, and combination with other therapies.

Going forward, neoadjuvant therapy shows promising prospects.

In addition, the toxicity of current and new immunotherapeutic combinations remains a critical point to address, and understanding the molecular mediators of immunotoxicity will go a long way toward controlling these side effects and improving patient management.








1. A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance. Nat Immunol. 2022 May; 23(5): 660–670.

A decade of checkpoint blockade immunotherapy for melanoma

(source:internet, reference only)

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