TY - JOUR
T1 - Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma
AU - Larrayoz, Marta
AU - Garcia-Barchino, Maria J.
AU - Celay, Jon
AU - Etxebeste, Amaia
AU - Jimenez, Maddalen
AU - Perez, Cristina
AU - Ordoñez, Raquel
AU - Cobaleda, Cesar
AU - Botta, Cirino
AU - Fresquet, Vicente
AU - Roa, Sergio
AU - Goicoechea, Ibai
AU - Maia, Catarina
AU - Lasaga, Miren
AU - Chesi, Marta
AU - Bergsagel, P. Leif
AU - Larrayoz, Maria J.
AU - Calasanz, Maria J.
AU - Campos-Sanchez, Elena
AU - Martinez-Cano, Jorge
AU - Panizo, Carlos
AU - Rodriguez-Otero, Paula
AU - Vicent, Silvestre
AU - Roncador, Giovanna
AU - Gonzalez, Patricia
AU - Takahashi, Satoru
AU - Katz, Samuel G.
AU - Walensky, Loren D.
AU - Ruppert, Shannon M.
AU - Lasater, Elisabeth A.
AU - Amann, Maria
AU - Lozano, Teresa
AU - Llopiz, Diana
AU - Sarobe, Pablo
AU - Lasarte, Juan J.
AU - Planell, Nuria
AU - Gomez-Cabrero, David
AU - Kudryashova, Olga
AU - Kurilovich, Anna
AU - Revuelta, Maria V.
AU - Cerchietti, Leandro
AU - Agirre, Xabier
AU - San Miguel, Jesus
AU - Paiva, Bruno
AU - Prosper, Felipe
AU - Martinez-Climent, Jose A.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/3
Y1 - 2023/3
N2 - The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK–MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.
AB - The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK–MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.
UR - http://www.scopus.com/inward/record.url?scp=85150044026&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85150044026&partnerID=8YFLogxK
U2 - 10.1038/s41591-022-02178-3
DO - 10.1038/s41591-022-02178-3
M3 - Article
C2 - 36928817
AN - SCOPUS:85150044026
SN - 1078-8956
VL - 29
SP - 632
EP - 645
JO - Nature Medicine
JF - Nature Medicine
IS - 3
ER -