1067P - Discovery of a new CD4+ T cell cluster that correlates PD-1 blockade efficacy

Background

CD4⁺ T-cell immunity, which helps clonal proliferation, migration, and cancer cell-killing activity of CD8⁺ T cells to drive cancer immunity cycle, is essential in antitumor immune responses. Important traits that determine T cell function include the T cell receptor (TCR) clonotype, which determines antigen specificity, and the state of functional transition from naïve to effector cells that occurs upon T-cell priming. In addition, CD4⁺ T cells have another important differentiation trait, polarity as helper T cells. The type 1 helper CD4⁺ T cell (Th1) is thought to be important for anti-tumor immunity, but the Th17 has also been reported to be important, and the details remain unclear.

Methods

To identify the CD4⁺ T cell clusters responsible for antitumor immunity, we simultaneously analyzed the naïve-effector state, Th polarization, and TCR clonotype based on single-cell RNA sequencing and mass cytometry analysis of peripheral blood of lung cancer patients prior to 1^st line PD-1 blockade therapy (n=60).

Results

Unsupervised clustering analysis uncovered the presence of a new CD4⁺ T cell meta-cluster in CD62L^low CD4⁺ T-cell subpopulation containing multicellular clonotypes associated with efficacy for PD-1 blockade therapy. The CD4⁺ T cell meta-cluster consisted of CXCR3⁺CCR4^-CCR6⁺ and CXCR3^-CCR4^-CCR6⁺ cells, which are different from Th1 or Th17 in gene expression and methylome patterns, and was characterized by high expression of IL-7 receptor and TCF7. Their frequency in peripheral blood was significantly correlated with progression-free survival and overall survival of lung cancer patients after PD-1 blockade therapy. In addition, the CD4⁺ meta-cluster in peripheral blood was correlated with CD4⁺ T cell infiltration in the tumor microenvironment, whereas peripheral Th1 correlated with local CD8⁺ T-cell infiltration.

Conclusions

In light of these findings, we propose that the CD62L^low CCR4^-CCR6⁺ CD4⁺ T cells form a novel meta-cluster. Predictive potential on the immune status from peripheral blood samples due to the T-cell association between systemic and local immunity may pave the way for new personalized antitumor immunotherapy strategies for patients.

Clinical trial identification

Editorial acknowledgement

editage

Legal entity responsible for the study

The authors.

Funding

KAKENHI program of the Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development grant

Disclosure

H. Kagamu: Financial Interests, Personal, Invited Speaker: Ono Pharm. Inc., BMS, AstraZeneca, Chugai Pharm. Inc.; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Ono Pharm. Inc., Chugai Pharm. Inc., Taiho Pharm. Inc. S. Kitano: Financial Interests, Institutional, Research Grant: Eisai, Boehringer Ingelheim, Astellas Pharma, Gilead Sciences, Regeneron, Takara Bio, Ono pharma, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Nippon Kayaku, Kyowa Hakko Kirin, Celgene, Eisai, Ono Pharma, Bristol-Myers Squibb, GlaxoSmithKline, AstraZeneca, Chugai, Ayumi Pharma, Rakuten Medical, Pfizer, Sanofi, Sumitomo Dainippon Pharma. All other authors have declared no conflicts of interest.