Abstract 5208: Circulating T cell: B cell: NK cell axis associated with response to pembrolizumab plus doxorubicin in patients with metastatic triple negative breast cancer
Authors: Egelston Colt A. , Guo Weihua , Lee Peter P. , Yost Susan E. , Waisman James R. , Yuan Yuan 
Published: June 2022

Abstract
Introduction: The use of immune checkpoint inhibitors (ICI) in combination with chemotherapy is now standard of care for patients with programmed death ligand 1-positive (PD-L1+) metastatic triple negative breast cancer (mTNBC). However, the mechanisms of response to ICIs are still poorly understood in patients with mTNBC. Here we investigate immune correlates of response in patients with mTNBC treated with programmed cell death protein 1 (PD-1) receptor-targeting pembrolizumab and doxorubicin (n=9).
Methods: Patients received pembrolizumab and doxorubicin every 3 weeks for a total of 6 cycles followed by pembrolizumab maintenance until disease progression. Objective response rates (ORR per RECIST 1.1) were: N=1 complete response (CR), N=4 partial responses (PR), N=3 stable disease (SD), and N=1 progression of disease (PD). Baseline tumor biopsies were collected for PD-L1 (22C3 antibody) and TILs analysis, and peripheral blood was collected for immune correlatives. Circulating peripheral blood mononuclear cells (PBMCs) were assessed by high parameter flow cytometry with samples collected at timepoints cycle 1 day 1 (C1D1), cycle 2 day 1 (C2D1), and cycle 3 day 1 (C3D1)
Results: No association between response and tumor infiltrating lymphocyte (TIL) scoring or PD-L1 expression were observed. Circulating exhausted CD8+ T cells (PD-1 high CD39+) were identified at baseline in all patients, with the patient with PD having a low frequency of exhausted CD8+ T cells (0.08% in PD vs. 0.3% mean in CR/PR/SD) at baseline. In the patient with PD, the following results were observed relative to other patients: high levels of antibody-secreting B cells (ASC, 15.2% in PD vs. 1.5% mean in CR/PR/SD), CD4+ follicular helper T cells (Tfh, 8.47% PD vs. 2.6% mean in CR/PR/SD), and terminally differentiated NK cells (11.0% PD vs. 6.3% mean CR/PR/SD) at baseline. From baseline to C2D1, the patient who achieved CR demonstrated robust expansion of exhausted CD8+ T cells (4.4-fold change in CR vs. 1.4-fold change in PR/SD/PD).
Conclusion: Our data suggests that both baseline immune profile ‘setpoints’ and dynamic remodeling of immune features, including expansion of exhausted CD8+ T cells, are associated with response to ICIs in patients with mTNBC. Lack of response to ICIs is defined not only by a lack of CD8+ T cell expansion, but also by high levels of circulating ASCs, Tfh, and terminal NK cells at baseline. Additional studies to further explore and validate features of this T cell: B cell: NK cell axis and response to ICIs in patients with mTNBC are ongoing.
Citation Format: Colt A. Egelston, Weihua Guo, Peter P. Lee, Susan E. Yost, James R. Waisman, Yuan Yuan. Circulating T cell: B cell: NK cell axis associated with response to pembrolizumab plus doxorubicin in patients with metastatic triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5208.