Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Tumor immune cell composition critically impacts immunotherapy response.
• Intratumoral immune cell heterogeneity and dynamics in human cancers are not well understood.

Purpose of the Study:

• To characterize conserved intratumoral CD4 and CD8 T cell behaviors in melanoma.
• To investigate the progression and characteristics of CD8 T cell states within the tumor microenvironment.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of immune infiltrates from 25 melanoma patients.
• Analysis of T cell receptor (TCR) sharing data.
• Assessment of gene expression signatures related to T cell function and proliferation.

Main Results:

• Identified a continuum of CD8 T cell states from transitional effectors to a dysfunctional phenotype.
• Rare CD8 T cells expressed a full cytotoxic gene set, appearing independent of transitional and dysfunctional states.
• Dysfunctional CD8 T cells represent the primary proliferating immune cell population within tumors.
• The intensity of the dysfunctional signature correlated with tumor reactivity.

Conclusions:

• Human tumor-infiltrating CD8 T cells previously termed 'exhausted' are actually a dynamic, proliferating, and clonal population.
• These findings offer new insights into T cell behavior within the tumor microenvironment and its implications for immunotherapy.