The Ectonucleotidase CD39 Identifies Tumor-reactive CD8 T cells Predictive of Immune Checkpoint Blockade Efficacy in Human Lung Cancer

Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8 T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8 T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39 CD8 T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39 CD8 T cells. Higher baseline frequency of CD39 CD8 T cells conferred improved clinical outcomes 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. These findings highlight CD39 as a proxy of tumor-reactive CD8 T cells in human lung cancer.

Citing Articles

Tissue-Resident Memory CD8+ T Cells: Differentiation, Phenotypic Heterogeneity, Biological Function, Disease, and Therapy.

Xu L, Ye L, Huang Q MedComm (2020). 2025; 6(3):e70132.

PMID: 40066223 PMC: 11892159. DOI: 10.1002/mco2.70132.

A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types.

Zeng Z, Zhang T, Zhang J, Li S, Connor S, Zhang B Nat Commun. 2025; 16(1):1070.

PMID: 39900903 PMC: 11791090. DOI: 10.1038/s41467-024-55059-3.

Liver metastases of colorectal cancer contain different subsets of tissue-resident memory CD8 T cells correlated with a distinct risk of relapse following surgery.

Abdeljaoued S, Doussot A, Kroemer M, Laloy E, Pallandre J, El Kaddissi A Oncoimmunology. 2025; 14(1):2455176.

PMID: 39844661 PMC: 11760230. DOI: 10.1080/2162402X.2025.2455176.

Elucidating stearoyl metabolism and NCOA4-mediated ferroptosis in gastric cancer liver metastasis through multi-omics single-cell integrative mendelian analysis: advancing personalized immunotherapy strategies.

Yang Z, Chen Y, Miao Y, Yan H, Chen K, Xu Y Discov Oncol. 2025; 16(1):46.

PMID: 39812999 PMC: 11735723. DOI: 10.1007/s12672-025-01769-z.

Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition.

Glaviano A, Lau H, Carter L, Lee E, Lam H, Okina E J Hematol Oncol. 2025; 18(1):6.

PMID: 39806516 PMC: 11733683. DOI: 10.1186/s13045-024-01634-6.

References

Simoni Y, Becht E, Fehlings M, Loh C, Koo S, Teng K . Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 2018; 557(7706):575-579. DOI: 10.1038/s41586-018-0130-2. View

Miller B, Sen D, Al Abosy R, Bi K, Virkud Y, LaFleur M . Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019; 20(3):326-336. PMC: 6673650. DOI: 10.1038/s41590-019-0312-6. View

Helmink B, Reddy S, Gao J, Zhang S, Basar R, Thakur R . B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020; 577(7791):549-555. PMC: 8762581. DOI: 10.1038/s41586-019-1922-8. View

Li H, van der Leun A, Yofe I, Lubling Y, Gelbard-Solodkin D, van Akkooi A . Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma. Cell. 2019; 176(4):775-789.e18. PMC: 7253294. DOI: 10.1016/j.cell.2018.11.043. View

Zehir A, Benayed R, Shah R, Syed A, Middha S, Kim H . Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017; 23(6):703-713. PMC: 5461196. DOI: 10.1038/nm.4333. View

Reck M, Rodriguez-Abreu D, Robinson A, Hui R, Csoszi T, Fulop A . Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016; 375(19):1823-1833. DOI: 10.1056/NEJMoa1606774. View

Scheper W, Kelderman S, Fanchi L, Linnemann C, Bendle G, de Rooij M . Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat Med. 2018; 25(1):89-94. DOI: 10.1038/s41591-018-0266-5. View

Verma V, Shrimali R, Ahmad S, Dai W, Wang H, Lu S . PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1CD38 cells and anti-PD-1 resistance. Nat Immunol. 2019; 20(9):1231-1243. PMC: 7472661. DOI: 10.1038/s41590-019-0441-y. View

Horn L, Mansfield A, Szczesna A, Havel L, Krzakowski M, Hochmair M . First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018; 379(23):2220-2229. DOI: 10.1056/NEJMoa1809064. View

10.

Yeong J, Suteja L, Simoni Y, Lau K, Tan A, Li H . Intratumoral CD39CD8 T Cells Predict Response to Programmed Cell Death Protein-1 or Programmed Death Ligand-1 Blockade in Patients With NSCLC. J Thorac Oncol. 2021; 16(8):1349-1358. DOI: 10.1016/j.jtho.2021.04.016. View

11.

Chowell D, Morris L, Grigg C, Weber J, Samstein R, Makarov V . Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2017; 359(6375):582-587. PMC: 6057471. DOI: 10.1126/science.aao4572. View

12.

Gros A, Parkhurst M, Tran E, Pasetto A, Robbins P, Ilyas S . Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016; 22(4):433-8. PMC: 7446107. DOI: 10.1038/nm.4051. View

13.

Burr M, Sparbier C, Chan K, Chan Y, Kersbergen A, Lam E . An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer. Cancer Cell. 2019; 36(4):385-401.e8. PMC: 6876280. DOI: 10.1016/j.ccell.2019.08.008. View

14.

Riaz N, Havel J, Makarov V, Desrichard A, Urba W, Sims J . Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017; 171(4):934-949.e16. PMC: 5685550. DOI: 10.1016/j.cell.2017.09.028. View

15.

Friedman J, Hastie T, Tibshirani R . Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw. 2010; 33(1):1-22. PMC: 2929880. View

16.

Gallardo H, Tan C, Ory D, Sadelain M . Recombinant retroviruses pseudotyped with the vesicular stomatitis virus G glycoprotein mediate both stable gene transfer and pseudotransduction in human peripheral blood lymphocytes. Blood. 1997; 90(3):952-7. View

17.

Terranova-Barberio M, Pawlowska N, Dhawan M, Moasser M, Chien A, Melisko M . Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020; 11(1):3584. PMC: 7367885. DOI: 10.1038/s41467-020-17414-y. View

18.

Caushi J, Zhang J, Ji Z, Vaghasia A, Zhang B, Hsiue E . Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature. 2021; 596(7870):126-132. PMC: 8338555. DOI: 10.1038/s41586-021-03752-4. View

19.

Sade-Feldman M, Yizhak K, Bjorgaard S, Ray J, de Boer C, Jenkins R . Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2018; 175(4):998-1013.e20. PMC: 6641984. DOI: 10.1016/j.cell.2018.10.038. View

20.

Ishihara M, Kitano S, Kageyama S, Miyahara Y, Yamamoto N, Kato H . NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release syndrome. J Immunother Cancer. 2022; 10(6). PMC: 9244667. DOI: 10.1136/jitc-2021-003811. View