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Single-cell profiling of acral melanoma infiltrating lymphocytes reveals a suppressive tumor microenvironment

ABSTRACT: Single-cell profiling of acral melanoma infiltrating lymphocytes reveals a suppressive tumor microenvironment

PROVIDER: PRJNA1013554 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25932613_1.fastq.gz	Fastqsanger.gz
	SRR25932613_2.fastq.gz	Fastqsanger.gz
	SRR25932614_1.fastq.gz	Fastqsanger.gz
	SRR25932614_2.fastq.gz	Fastqsanger.gz
	SRR25932615_1.fastq.gz	Fastqsanger.gz

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Single-cell profiling of acral melanoma infiltrating lymphocytes reveals a suppressive tumor microenvironment

Project description:Acral lentiginous melanoma (ALM) is the most common melanoma subtype in non-Caucasians. Despite advances in cancer immunotherapy, current immune checkpoint inhibitors remain unsatisfactory for ALM. Hence, we conducted comprehensive immune profiling using single-cell phenotyping with reactivity screening of the T cell receptors of tumor-infiltrating T lymphocytes (TILs) in ALM. Compared with cutaneous melanoma, ALM showed a lower frequency of tumor-reactive CD8 clusters and an enrichment of regulatory T cells with direct tumor recognition ability, suggesting a suppressive immune microenvironment in ALM. Tumor-reactive CD8 TILs showed heterogeneous expression of coinhibitory molecules, including KLRC1 (NKG2A), in subpopulations with therapeutic implications. Overall, our study provides a foundation for enhancing the efficacy of immunotherapy in ALM.

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Project description:This analysis reveals the different gene expression profiles between human melanoma tumor infiltrating lymphocytes subsets CD8+CD28+ and CD8+CD28-. Adoptive cell therapy (ACT) is an effective approach that removes tumor-infiltrating lymphocytes (TILs) from this suppressive tumor microenvironment and expands and activates CD8+ and CD4+ T cells in vitro, differentiating them into potent anti-tumor effector cells that can be re-introduced back into patients. One of the key problems that may limit tumor regression and long-term durable clinical responses in ACT is the persistence of TILs following infusion. Our study has indicated that ex vivo expanded TILs to be hypo-responsive to peptide re-stimulation, manifested in slow entry into cell cycle and increased apoptosis. Phenotypic and functional analysis using a number of different T-cell differentiation markers found that CD28 was markedly down-modulated in post-REP cells, while CD27 and CD57 levels showed no statistically-relevant changes in expression. Here on a global gene expression level, microarray gene chip analysis of sorted CD8+CD28+ and CD8+CD28- post-REP TILs revealed a number of key differences in their gene expression profiles; notably, an increase in KIR family member expression, loss of p53-binding proteins, and lower CD127/IL-7Ra gene expression found in the CD28- population. On top of advancing T cell phenotype, reactivation and memory, this set of data may also provide insight for ACT clinical protocol optimization to improve TIL response in vivo.

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