{"doi":"10.1136/jitc-2020-002084","title":"Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer","abstract":"Background Single-agent pembrolizumab treatment of hormone receptor-positive metastatic breast cancer (MBC) has demonstrated modest clinical responses. Little is known about potential biomarkers or mechanisms of response to immune checkpoint inhibitors (ICIs) in patients with HR+ MBC. The present study presents novel immune correlates of clinical responses to combined treatment with CDK4/6i and ICI. Methods A combined analysis of two independent phase I clinical trials treating patients with HR+ MBC was performed. Patients treated with the combination of the CDK4/6i palbociclib+the ICI pembrolizumab+the aromatase inhibitor (AI) letrozole (palbo+pembro+AI) were compared with patients treated with pembrolizumab+AI (pembro+AI). Peripheral blood mononuclear cells collected at pretreatment, 3 weeks (cycle 2 day 1) and 9 weeks (cycle 4 day 1) were characterized by high-parameter flow cytometry to assess baseline immune subset composition and longitudinal changes in response to therapy. Results In the peripheral blood, higher pretreatment frequencies of effector memory CD45RA + CD8 + T cells and effector memory CD4 + T cells were observed in responders to palbo+pembro+AI. In contrast, this was not observed in pembro+AI-treated patients. We further characterized T-cell subsets of effector-like killer cell lectin-like receptor subfamily G member 1 (KLRG1 + ) ICOS + CD4 + T cells and KLRG1 + CD45RA + CD8 + T cells as baseline biomarkers of response. In comparison, pretreatment levels of tumor-infiltrating lymphocyte, tumor mutation burden, tumor programmed death-ligand 1 expression, and overall immune composition did not associate with clinical responses. Over the course of treatment, significant shifts in myeloid cell composition and phenotype were observed in palbo+pembro+AI-treated patients, but not in those treated with pembro+AI. We identified increased fractions of type 1 conventional dendritic cells (cDC1s) within circulating dendritic cells and decreased classical monocytes (cMO) within circulating monocytes only in patients treated with palbociclib. We also demonstrated that in palbociclib-treated patients, cDC1 and cMO displayed increased CD83 and human leukocyte antigen-DR isotype (HLA-DR) expression, respectively, suggesting increased maturation and antigen presentation capacity. Conclusions Pre-existing circulating effector CD8 + and CD4 + T cells and dynamic modulation of circulating myeloid cell composition denote response to combined pembrolizumab and palbociclib therapy for patients with HR+ MBC. Trial registration number NCT02778685 and NCI02648477.","journal":"Journal for ImmunoTherapy of Cancer","year":2021,"id":167218,"datarank":1.31760028571628,"base_score":3.4965075614664802,"endowment":3.4965075614664802,"self_citation_contribution":0.5244761342199721,"citation_network_contribution":0.793124151496308,"self_endowment_contribution":0.5244761342199721,"citer_contribution":0.793124151496308,"corpus_percentile":null,"corpus_rank":null,"citation_count":32,"citer_count":29,"citers_with_citation_signal":26,"citers_with_endowment":26,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02778685"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":660172,"name":"Weihua Guo","orcid":"0000-0002-9580-513X","position":1,"is_corresponding":false},{"id":461448,"name":"Susan E. Yost","orcid":"0000-0002-9422-0316","position":2,"is_corresponding":false},{"id":461447,"name":"Jin Sun Lee","orcid":"0000-0003-2965-7009","position":3,"is_corresponding":false},{"id":694053,"name":"D. L. ROSE","orcid":"0000-0003-1430-5692","position":4,"is_corresponding":false},{"id":294147,"name":"Christian Avalos","orcid":"0000-0001-8852-9520","position":5,"is_corresponding":false},{"id":307736,"name":"Jian Ye","orcid":"0000-0002-7168-0117","position":6,"is_corresponding":false},{"id":380347,"name":"Paul Frankel","orcid":"0000-0003-2231-6121","position":7,"is_corresponding":false},{"id":582368,"name":"Daniel Schmolze","orcid":"0000-0002-6947-2546","position":8,"is_corresponding":false},{"id":294149,"name":"James Waisman","orcid":"0000-0003-2896-4146","position":9,"is_corresponding":false},{"id":336330,"name":"Peter Lee","orcid":"0000-0002-3898-8881","position":10,"is_corresponding":false},{"id":443405,"name":"Yuan Yuan","orcid":"0000-0001-7440-8939","position":11,"is_corresponding":false},{"id":564708,"name":"Colt A. Egelston","orcid":"0000-0001-8440-1271","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T23:45:54.042727Z","pmid":"33757987","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}