Ag-specific type 1 CD8 effector cells enhance methotrexate-mediated antitumor responses by modulating endogenous CD49b-expressing CD4 and CD8 T effector cell subpopulations producing IL-10.
The chemotherapeutic agent methotrexate is widely used in the treatment of breast cancer. Although its mechanism-of-action has been defined, less is known about its interaction with Ag-specific T cell-mediated antitumor responses. Type 1 CD8 T cell-mediated immune responses (Tc1) are cytolytic, produce IFN-gamma and are associated with effective antitumor responses. Using a murine transgenic TCR tumor model, we show that single-dose-treatment with methotrexate enhanced CD8-mediated type 1 antitumor responses when administered three days prior to Tc1 effector cell transfer. Co-treatment with methotrexate not only enhanced donor Tc1 cell accumulation and persistence at sites of primary tumor growth, but also promoted elevated levels of activated CD25(+) expressing donor TIL cells. This correlated with a marked decrease in the appearance of endogenous differentiated (CD44(High)) CD3/CD8/CD49b and CD3/CD4/CD49b tumor-infiltrating effector T cells at both early (Days 1-8) and late (Days 12-20) stages following treatment when compared to that of corresponding groups receiving either MTX or Tc1 cell transfer alone. Moreover, such cellular response kinetics appeared to further correlate with the down-regulation of endogenous CD4/CD44(High)/CD49b effector T cells producing IL-10 and delays in tumor growth in vivo. This suggested that Ag-specific Tc1 cell transfer, in combination with chemotherapy, can enhance antitumor responses by modulating select CD49b-expressing T effector/memory cell subpopulations involved in homeostasis and immune tolerance within the tumor environment. These studies offer insight into mechanisms that enhance T cell-based immunotherapy in cancer. Supplementary materials are available for this article. Go to the publisher's online edition of Immunological Investigations for the following free supplemental resource(s): Addendum 1.
Department of Internal Medicine, Texas Tech University School of Medicine, Amarillo, Texas 79106, USA. mark.dobrzanski@ttuhsc.edu
Mark J
MJ
Dobrzanski
Joyce B
JB
Reome
James C
JC
Hylind
Kathleen A
KA
Rewers-Felkins
Khaliquzzaman
K
Abdulsamad
Shawna L
SL
Adams
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D019264:Adoptive Transfer; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D039421:Integrin alpha2 / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000628:therapy*; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
D000964:Antimetabolites, Antineoplastic; D039421:Integrin alpha2; D016753:Interleukin-10; D008727:Methotrexate