Antitumor PD-1⁻ CD8⁺ T-cell Subsets Expand upon Anti–PD-1/TIM3 Therapy

Immune checkpoint blockade (ICB) therapy targeting inhibitory receptors, such as PD-1 and TIM3, has been clinically efficacious. Having previously shown that TIM3⁺PD-1⁺ CD8⁺ tumor-infiltrating lymphocytes (TIL) are highly dysfunctional and that TIM3⁻PD-1⁻ TILs exhibit the potential for effector function, Kurtulus, Madi, and colleagues profiled the transcriptome of both TIM3⁺PD-1⁺ and TIM3⁻PD-1⁻ CD8⁺ TILs (expressing low and high dysfunction signature, respectively) after anti–PD-1/TIM3 treatment to identify the effects of ICB on both of these populations. Computational analyses revealed that both TIM3⁻PD-1⁻ and TIM3⁺PD-1⁺ CD8⁺ TILs exhibit increased expression of genes associated with effector functions, with TIM3⁻PD-1⁻ CD8⁺ TILs exhibiting the most significant change. Further, they showed that anti–PD-1/TIM3 therapy expanded PD-1⁻ CD8⁺ TILs, which could give rise to both PD-1⁻ and PD-1⁺ progeny upon adoptive transfer into mice harboring OVA-expressing tumors. Further characterization of PD-1⁻ CD8⁺ TILs identified three distinct subsets with features of naïve-, memory precursor–, and effector-like CD8⁺ T cells. ICB therapy resulted in a decrease of the naïve-like PD-1⁻ CD8⁺ TILs and a concomitant increase in the memory precursor– and effector-like PD-1⁻ CD8⁺ TILs. The memory precursor–like PD-1⁻ CD8⁺ TILs were shown to express TCF1 (encoded by Tcf7), which was critical for their maintenance and response to anti–PD-1/TIM3 as well as a TLR9 agonist in tumor-bearing mice. Taken together, these results describe how immune checkpoint blockade affects CD8⁺ TIL populations to unleash the antitumor CD8⁺ T-cell response and identifies an early memory-precursor population that may serve as a biomarker for response to immunotherapy.

Kurtulus S, Madi A, Escobar G, Klapholz M, Nyman J, Christian E, et al. Checkpoint blockade immunotherapy induces dynamic changes in PD-1⁻CD8⁺ tumor-infiltrating T cells. Immunity 2019;50:181–94.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.