Botta and Perez et al. showed that as multiple myeloma (MM) evolved in patients, the “large” (most expanded) BM T cell clones that developed were enriched in CD8+GZMK+PRF+, effector GZMK+, and TOX+ T cells, with increased PD-1 and TIGIT expression and a high CD27-:CD27+ ratio compared to BM T cells (which also had greater TCR diversity) in healthy adults. In a genetically engineered mouse model showing similarities to human MM, anti-PD-1 with, but not without, anti-LAG3 or anti-TIGIT treatment delayed MM growth. Analysis of 453 patients in phase 3 MM trials of lenalidomide-based treatment combinations suggested the CD27-:CD27+ ratio had prognostic value.
Contributed by Paula Hochman
ABSTRACT: Tumor recognition by T cells is essential for antitumor immunity. A comprehensive characterization of T cell diversity may be key to understanding the success of immunomodulatory drugs and failure of PD-1 blockade in tumors such as multiple myeloma (MM). Here, we use single-cell RNA and T cell receptor sequencing to characterize bone marrow T cells from healthy adults (n = 4) and patients with precursor (n = 8) and full-blown MM (n = 10). Large T cell clones from patients with MM expressed multiple immune checkpoints, suggesting a potentially dysfunctional phenotype. Dual targeting of PD-1 + LAG3 or PD-1 + TIGIT partially restored their function in mice with MM. We identify phenotypic hallmarks of large intratumoral T cell clones, and demonstrate that the CD27- and CD27+ T cell ratio, measured by flow cytometry, may serve as a surrogate of clonal T cell expansions and an independent prognostic factor in 543 patients with MM treated with lenalidomide-based treatment combinations.
Author Info: (1) Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy. cirino.botta@unipa.it. Clinica Universi
Author Info: (1) Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy. cirino.botta@unipa.it. Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. cirino.botta@unipa.it. (2) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (3) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (4) Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigacin del Cancer (IBMCC-USAL, CSIC), CIBER-ONC number CB16/12/00233, Salamanca, Spain. (5) Hospital Universitario 12 de Octubre, CIBER-ONC number CB16/12/00369, Madrid, Spain. (6) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (7) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (8) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (9) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (10) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (11) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (12) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (13) Department of Informatics, Systems and Communication, University of Milano-Bicocca, Milan, Italy. (14) Department of Environmental Sciences, Informatics and Statistics, Ca' Foscari University of Venice, Venice, Italy. Bicocca Bioinformatics, Biostatistics and Bioimaging Centre-B4, Milan, Italy. (15) Department of Informatics, Systems and Communication, University of Milano-Bicocca, Milan, Italy. Bicocca Bioinformatics, Biostatistics and Bioimaging Centre-B4, Milan, Italy. (16) Department of Oncohematology, "Annunziata" Hospital, Cosenza, Italy. (17) Medical Oncology Unit, Great Metropolitan Hospital "Riuniti" of Reggio Calabria, Reggio Calabria, Italy. (18) Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy. (19) Institut Catal d'Oncologia i Institut Josep Carreras, Badalona, Spain. (20) Servicios de Medicina Interna y Hematologa, Hospital de Cabuees, Gijn, Asturias, Spain. (21) Institut Catal d'Oncologia-Hospitalet, Instituto de Investigacin Biomdica de Bellvitge (IDIBELL), Barcelona, Spain. (22) Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain. (23) Hospital Universitario Puerta de Hierro, Majadahonda, Spain. (24) Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain. (25) Hospital Vall d'Hebron, Barcelona, Spain. (26) Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain. (27) Hospital Son Llatzer, Palma de Mallorca, Spain. (28) Hospital Clnico Lozano Blesa, Zaragoza, Spain. (29) Hospital Son Espases, Palma de Mallorca, Spain. (30) Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. (31) Unite de Genomique du Myelome, IUC-T Oncopole, Toulouse, France. (32) Department of Hematology, ASST Spedali Civili di Brescia, Brescia, BS, Italy. (33) Cancer Research Center (IBMCC-CSIC/USAL-IBSAL), CIBER-ONC number CB16/12/00400, Salamanca, Spain. Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca, Salamanca, Spain. (34) Hospital Universitario 12 de Octubre, CIBER-ONC number CB16/12/00369, Madrid, Spain. (35) Hospital Clnic IDIBAPS, Barcelona, Spain. (36) Hospital Universitario 12 de Octubre, CIBER-ONC number CB16/12/00369, Madrid, Spain. (37) Hospital Clnic IDIBAPS, Barcelona, Spain. (38) Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigacin del Cancer (IBMCC-USAL, CSIC), CIBER-ONC number CB16/12/00233, Salamanca, Spain. (39) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (40) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. (41) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), CCUN, Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain. bpaiva@unav.es.
