The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Chow A., Uddin, F., Z., Liu, M. et al. Immunity. 56 (1): 93-106. (2022).
doi: 10.1016/j.immuni.2022.12.001.
Summary of the findings
Summary of the findings
The repertoire of tumor-infiltrating lymphocytes (TILs) can be vast, and many of these TILs are not endowed with tumor reactivity. While a number of reports have shown that tumor-reactive CD8+ TILs express CD39, few reports have demonstrated that conversely, CD39 can be leveraged to serve as a proxy of tumor-reactive CD8 T cells. Using single-cell CITE/RNA/TCRseq, we show that CD39+ CD8 T cells in human lung cancers demonstrate transcriptional and proteomic features of exhaustion, tumor reactivity, and clonal expansion. Moreover, T cell receptor (TCR) cloning revealed that CD39 expression enriched for tumor-reactive CD8+ T cell clones in human lung cancer biospecimens. We observed that expression of CD39 in human CD8+ T cells was driven by antigen-specific TCR stimulation that durably increased after antigen stimulation and was proportional to antigen density and TCR signal strength. Flow cytometry of 440 lung cancer specimens revealed that CD39 level on CD8+ T cells is only weakly correlated with tumoral features that currently guide lung cancer therapy, such as histology, driver mutation, PD-L1 and tumor mutation burden (TMB). Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Baseline CD39 levels on CD8+ T cells were associated with improved clinical outcomes, but not immune-related adverse events, from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. This comprehensive profiling of the clinical, pathological and molecular features highlights the utility of CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer.
Future impact
The success of ICB is dependent on the presence of an adequate number of endogenous tumor-reactive CD8+ T cells. CD39 expression on CD8+ T cells represents a simple proxy for the size of this endogenous tumor-reactive repertoire that can prioritize ICB therapies for those patients most likely to benefit. Furthermore, CD39 expression on CD8+ T cells can be utilized to enrich for tumor-reactive TCR candidates that leveraged can be in adoptive T cell therapies.
