The research team found that dysfunctional CD8+ T cell abundance is associated with immune tumor recognition.“High levels of dysfunctionality in CD8[+] T cells is associated with tumor reactivity,” they reported.1 T cell reactivity appeared to depend on human leukocyte antigen (HLA) class I molecules. Dysfunctional cells appeared to exhibit increased CD39 (ENTPD1)and CD103 (ITGAE) expression compared to transitional cells, and upregulated expression of KLRG1, consistent with previous research on gene expression and CD8+ T cell reactivity.1  

“It is a neat study that uses some more recent sequencing technologies to empirically show what us tumor immunologists have been gradually realizing over recent years,” said John Reiser, a graduate researcher who studies CD8+ T-cell differentiation and tumor immunology at the University of Maryland School of Medicine in Baltimore.3

“Before the advent of single-cell analysis platforms, we viewed immune cell subsets as bulk populations,” he told Cancer Therapy Advisor. “We were able to make generalized claims about, say, the responding population of tumor infiltrating lymphocytes (TILs). Now, and as this paper eloquently demonstrates, we know that CD8+ T cells in the tumor microenvironment represent a heterogeneous population of highly transitory cells. “The authors demonstrate that within the CD8+ T cell compartment, there is considerable heterogeneity in the subset composition, even with regards to T cell receptor clonality.

“One of the difficulties we have as tumor immunologistsis defining T cell fates during an antitumor immune response, as they are very transient,” Reiser explained. “We define exhausted or dysfunctional T cells based on surface marker expression, cytokine production and proliferative rates, yet these are often arbitrary classifications.”

Nor is distinguishing between cytotoxic and dysfunctionalCD8+ T cells a simple matter, Reiser cautioned. The study authors themselves acknowledged that the border between classifying cytotoxic CD8+ T cells and dysfunctional CD8+ T cells is “diffuse,” he noted.

“These likely represent the transitory, dysfunctional cells,” he explained. “It’s hard to time-stamp at what point a cell becomes dysfunctional and at what point these dysfunctional cells are no longer beneficial to the patient.”