Highlights in Cancer Research: May 2023

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).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

Use the dropdown menu or ‘Previous’ and ‘Next’ buttons to navigate the list.

4. The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer

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

We performed single cell sequencing (scCITE/TCR/RNA) of T cells from lung cancer biospecimens in order to link protein CD39 expression with transcriptional profile and TCR sequence. Using TCR cloning, we demonstrated that CD39+ CD8+ T cells are enriched for tumor reactivity and that CD39 expression is a durable marker of TCR recognition of cognate peptide: MHC I on tumor cells. We observed that non-KRAS/HER2-altered lung adenocarcinoma (LUAD) tumors, which are typically not associated with tobacco use had lower CD39 expression on CD8+ T cells. In contrast, KRAS- and HER2-altered lung adenocarcinoma and squamous lung cancers had higher CD39 expression on CD8+ T cells. Surprisingly, small cell lung cancer tumors, respite their association with tobacco use and high tumor mutation burdens, had lower CD39 expression on CD8+ T cells. Finally, higher levels of CD39 expression on CD8+ T cells or higher transcriptional expression of a gene signature of CD39+ CD8+ T cells was associated with improved responses from immune checkpoint blockade therapy. Created with BioRender.com

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.

Read more in Immunity