Immune checkpoint blockade augments lymphodepleting chemotherapy-induced antitumor immunity by expanding effector CD8+ T cell clones.

Authors

Mariam Mathew George, Linda Hamadene, Yacine Marouf, Nicholas Ceglia, Daniel Hirschhorn, Isabell Schulze, Lauren Dong, Divya Venkatesh, Rachana R Maniyar, Sadna Budhu, Alan N Houghton, Benjamin D Greenbaum, Jedd D Wolchok, Allison S Betof, Taha Merghoub

Published in

Cancer research. Jun 22, 2026. Epub Jun 22, 2026.

Abstract

Cancer treatment using immune checkpoint blockade (ICB) with anti-PD-1 and anti-CTLA-4 has been successful. However, primary and acquired resistance limits clinical benefit. To improve the effectiveness of ICB therapies, strategies that reorchestrate anti-tumor immunity through mechanism-based drug combinations are being actively explored. The alkylating chemotherapeutic agent cyclophosphamide (CTX) has direct tumoricidal and immunomodulatory properties, including the induction of homeostatic proliferation of T cells. Since ICB suppresses inhibitory signals in T cells, ICB might be able to augment CTX-induced homeostatic proliferation of antigen-specific T cells, thereby resetting the T cell receptor (TCR) repertoire in favor of tumor-specific T cells. Here, we showed that a single dose of CTX one day prior to starting αPD-1+αCTLA-4 treatment was sufficient to delay tumor progression in established melanoma and prolong survival in tumor-bearing mouse models. These effects extended to other lymphodepleting treatments, such as gemcitabine and radiation therapy. The anti-tumor immune response was mainly driven by the clonal expansion of activated/effector CD8+ tumor infiltrating lymphocytes. Furthermore, combined CTX and αPD-1+αCTLA-4 treatment demonstrated efficacy across additional preclinical tumor models, including colorectal cancer and triple negative breast cancer. Overall, these findings highlight that the combination of CTX and ICB represents a clinically relevant approach in the treatment of immunotherapy-refractory tumors.

PMID:
42329854
Bibliographic data and abstract were imported from PubMed on 23 Jun 2026.

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