Yuan Yuan, Ph.D., medical oncologist, City of Hope, and Colt Egelston, Ph.D., assistant research professor at the Beckman Research Institute of the City of Hope. In this video, they speak about the AACR 2022 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.
Outline
In patients with programmed death ligand 1-positive (PD-L1+) metastatic triple negative breast cancer, the use of immune checkpoint inhibitors (ICI) in combination with chemotherapy is now the standard of care (mTNBC). However, the mechanisms of ICI response in patients with mTNBC remain unknown. We looked at immunological correlates of response in patients with mTNBC who were treated with the PD-1 receptor-targeting pembrolizumab and doxorubicin (n=9).
Methodologies:
Pembrolizumab and doxorubicin were given to patients every 3 weeks for a total of 6 cycles, followed by pembrolizumab maintenance until disease progression. The objective response rates (ORR) according to RECIST 1.1 were as follows: N=1 complete response (CR), N=4 partial responses (PR), N=3 stable disease (SD), and N=1 disease progression (PD). TILs and PD-L1 (22C3 antibody) analyses were performed on baseline tumor tissues, and peripheral blood was taken for immune correlates. High parameter flow cytometry was used to analyze circulating peripheral blood mononuclear cells (PBMCs) taken at timepoints cycle 1 day 1 (C1D1), cycle 2 day 1 (C2D1), and cycle 3 day 1 (C3D1) (C3D1)
Findings:
There was no correlation between response and tumor infiltrating lymphocyte (TIL) score or PD-L1 expression. At baseline, all patients had to circulate exhausted CD8+ T cells (PD-1 high CD39+), with the patient with PD having a low frequency of exhausted CD8+ T cells (0.08 percent in PD vs. 0.3 percent mean in CR/PR/SD). At baseline, the patient with PD had higher levels of antibody-secreting B cells (ASC, 15.2 percent in PD vs. 1.5 percent mean in CR/PR/SD), CD4+ follicular helper T cells (Tfh, 8.47 percent PD vs. 2.6 percent mean in CR/PR/SD), and terminally differentiated NK cells (11.0 percent PD vs. 6.3 percent mean CR/PR/SD). The patient who attained CR revealed a strong increase of depleted CD8+ T cells from baseline to C2D1 (4.4-fold change in CR vs. 1.4-fold change in PR/SD/PD).
Inference:
Our findings demonstrate that in patients with mTNBC, both baseline immunological profile ‘setpoints’ and dynamic remodeling of immune characteristics, such as an increase of fatigued CD8+ T cells, are linked with response to ICIs. Lack of response to ICIs is characterised by high numbers of circulating ASCs, Tfh, and terminal NK cells at baseline, as well as a lack of CD8+ T cell growth. Additional research is being conducted to investigate and validate the properties of this T cell: B cell: NK cell axis and response to ICIs in patients with mTNBC.