[Title]
CD39(+) tissue-resident memory CD8(+) T cells with a clonal overlap across compartments mediate antitumor immunity in breast cancer

[Author] Yong Joon Lee1,2†, Jee Ye Kim2†, Seung Hyuck Jeon1, Heejin Nam1, Jae Hyung Jung1, Minwoo Jeon1, Eui-Soon Kim1, Soong June Bae3, Juneyoung Ahn4, Tae-Kyung Yoo5, Woo Young Sun6, Sung Gwe Ahn3, Joon Jeong3, Su-Hyung Park1, Woo Chan Park5*, Seung Il Kim2*, Eui-Cheol Shin1*

1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
2Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
3-Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea.
4Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, Catholic University of Korea, Seoul 11765, Republic of Korea.
5Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, Catholic University of Korea, Seoul 06591, Republic of Korea.
6Department of Surgery, Daejeon St. Mary’s Hospital, College of Medicine, Catholic University of Korea, Seoul 34943, Republic of Korea.
*Corresponding author. Email: wcpark@catholic.ac.kr (W.C.P.); ecshin@kaist.ac.kr(E.-C.S.); skim@yuhs.ac (S.I.K.)
†These authors contributed equally to this work.

[Journal] 
SCIENCE IMMUNOLOGY, 26 Aug 2022, Vol 7, Issue 74

[Abstract]
Despite being a standard treatment option in breast cancer, immune checkpoint inhibitors (ICIs) are only efficacious for a subset of patients. To gain a better understanding of the antitumor immune response in breast cancer, we examined the heterogeneity of CD8⁺ T cells in tumors, metastatic lymph nodes (mLNs), and peripheral blood from patients with early breast cancer (n = 131). Among tissue-resident memory CD8⁺ T (T_RM) cells, including virus- and tumor-specific CD8⁺ T cells, CD39 expression was observed in a tumor-specific and exhausted subpopulation in both tumors and mLNs. CD39⁺ T_RM cells from tumors and mLNs exhibited a phenotypic similarity and clonally overlapped with each other. Moreover, tumor or mLN CD39⁺ T_RM cells clonally overlapped with CD39⁻ T_RM and non-T_RM cells in the same compartment, implying a tissue-specific differentiation process. These inter-subpopulationally overlapping CD39⁺ T_RM clonotypes were frequently detected among effector memory CD8⁺ T cells in peripheral blood, suggesting a systemic clonal overlap. CD39⁺ T_RM cell enrichment was heterogeneous among molecular subtypes of breast cancer, which is associated with the different role of antitumor immune responses in each subtype. In vitro blockade of PD-1 and/or CTLA-4 effectively restored proliferation of CD39⁺ T_RM cells and enhanced cytokine production by CD8⁺ T cells from tumors or mLNs, particularly in the presence of CD39⁺ T_RM enrichment. This suggests that CD39⁺ T_RM cells have a capacity for functional restoration upon ICI treatment. Thus, our study indicates that CD39⁺ T_RM cells with a clonal overlap across compartments are key players in antitumor immunity in breast cancer.