Impact of chemotherapy (chemo) on t-cell maturation and clonal proliferation in early-stage and metastatic breast cancer
2020 San Antonio Breast Cancer Symposium®
oregon; portland; chiles
Background Adaptive immunity is initiated by T-cell receptor (TCR) engagement with cognate tumor antigen, leading to T-cell maturation (i.e. conversion from naïve to effector state), clonal proliferation, and potentially tumor elimination. Therefore, broad T-cell repertoire diversity could be an important determinant of anti-tumor immunity. In breast cancer, chemo may facilitate adaptive immunity, but conversely may also be lymphotoxic. We characterize the impacts of curative-intent chemo and palliative combination chemo/immune checkpoint inhibition (ICI) on lymphocyte quantity, maturation, and clonal proliferation. Methods Peripheral blood mononuclear cells (PBMCs) were collected at baseline and serially in stage IIII subjects receiving curative-intent chemo (dose-dense doxorubicin, cyclophosphamide, paclitaxel, n=20), and in stage IV subjects receiving palliative ICI (pembrolizumab) plus chemo (paclitaxel, n=15; or capecitabine, n=14). Flow cytometry was conducted on fresh PBMCs to minimize cellular losses related to cryopreservation. DNA was extracted for T-cell clonality analysis using the immunoSEQ Assay (Adaptive Biotechnologies) at deep resolution. T-cell richness, calculated using the iChao1 richness estimator was used to assess overall T-cell diversity. Results Both dose-dense chemo and palliative chemo/ICI were lymphodepleting, however dose-dense chemo was associated with greater reductions in CD4+ naïve T cell count (week 8 counts 34% vs. 96% of baseline, p<.001) and T-cell richness (week 8 richness 57% vs 90% of baseline, p<.001). These effects were durable, with reductions in lymphocyte subsets (ALC, CD4, CD8, naïve, effector, and central memory subsets) and T-cell richness (estimated rearrangements 4.37 vs 3.29 x 10 5/sample) sustained at metastatic relapse. T-cell richness correlated with CD4+ naïve cell proportion (R2=0.52), suggesting a major contribution of CD4+ naïve cells to overall T-cell diversity. In this dataset, acute memory T-cell expansions were observed following initiation of chemo, but only among younger patients (age<60). Conclusions Curative-intent cytotoxic chemotherapy durably alters the quantity and diversity of peripheral T-cells, particularly of naïve cells, contributing to lymphopenia and reduced T-cell richness at metastatic relapse. Acute expansions of EM subsets were also observed but only in younger individuals. These contrasting immunologic effects highlight the potential importance of sequencing of ICI relative to chemo, and raise concerns regarding age-related thymic involution and immunosenescence. Ongoing research is warranted to investigate the predictive/prognostic utility of T-cell diversity/quantity in breast cancer, and whether thymic T-cell regeneration can be targeted therapeutically to enhance immunotherapy response, for example with cytokine therapies (IL-12 or IL-7, NCT04095689) or sex steroid inhibition (NCT03650894).
Women & Children
Earle A. Chiles Research Institute
Chun, Brie; Pucilowska, Joanna; Conrad, Valerie; Schmidt, Mark; Kim, Isaac; Fields, Paul; Conlin, Alison; McArthur, Heather; and Page, David B, "Impact of chemotherapy (chemo) on t-cell maturation and clonal proliferation in early-stage and metastatic breast cancer" (2020). Articles, Abstracts, and Reports. 4514.