Cyclophosphamide treatment induces rejection of established P815 mastocytoma by enhancing CD4 priming and intratumoral infiltration of P1E/H-2K(d) -specific CD8+ T cells

Int J Cancer. 2014 Jun 15;134(12):2841-52. doi: 10.1002/ijc.28617. Epub 2013 Nov 29.


There is increasing evidence that the effect of chemotherapy on tumor growth is not cell autonomous but relies on the immune system. The objective of this study was therefore to decipher the cellular and molecular mechanisms underlying the role of innate and adaptive immunity in chemotherapy-induced tumor rejection. Treatment of DBA/2 mice bearing P815 mastocytoma with cyclophosphamide induced rejection and long-term protection in a CD4- and CD8-dependent manner. A population of inflammatory-type dendritic cells was dramatically expanded in the lymph nodes of mice that rejected the tumor and correlated with CD4-dependent infiltration, in tumor bed, of tumor-specific CD8+ T lymphocytes. Our data point to a major role of CD4+ T cells in inducing chemokine expression in the tumor, provoking migration of tumor-specific CXCR3+ CD8+ T lymphocytes. Importantly, the analysis of CD8+ T cells specific to P1A/H-2L(d) and P1E/H-2K(d) revealed that cyclophosphamide altered the P815-specific CD8 T repertoire by amplifying the response specific to the mutated P1E antigen.

Keywords: chemokines; cyclophosphamide; dendritic cells; infiltration; tumor antigens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Cell Movement / immunology
  • Cell Proliferation
  • Cyclophosphamide / therapeutic use*
  • Dendritic Cells / immunology
  • H-2 Antigens / immunology
  • Integrin beta3 / immunology
  • Lymph Nodes / cytology
  • Lymphocyte Activation / immunology
  • Mastocytoma / drug therapy*
  • Mastocytoma / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Receptors, CXCR3 / metabolism


  • Antineoplastic Agents, Alkylating
  • Cxcr3 protein, mouse
  • H-2 Antigens
  • H-2K(K) antigen
  • ITGB3 protein, human
  • Integrin beta3
  • Receptors, CXCR3
  • Cyclophosphamide