High-dose cyclophosphamide induces specific tumor immunity with concomitant recruitment of LAMP1/CD107a-expressing CD4-positive T cells into tumor sites (original) (raw)

Cancer chemotherapy, particularly one usingregimens employing high-dose cytotoxic drugs such as cyclophosphamide (CTX), has been considered to be immune suppressive[Ed1]. On the contraryHowever, we observed that a single administration of high-dose CTX administration abolished the tumors arising from subcutaneous injection of a mouse hepatoma cell line, and subsequently induced specific tumor immunity. The aAbsence of T cells or Ddepletion of T cells, specifically CD4 + T cells, abrogated the CTX-mediated tumor regression[Ed2]. CTX treatment induced the rapid recruitment of CD4 + T cells into the tumors, and these recruited cells started toinitiated expression of LAMP1/CD107a, a cytotoxic granule molecule, LAMP1/CD107a, and granzyme B without in the absence of antigen presentation at draining lymph nodes and proliferation in the tumor tissues. Moreover, CTX enhanced the expression of a CC chemokine, CCL3, in tumor tissues, and CTX-mediated tumor regression was attenuated in mice deficient in CCR5, the receptor for this chemokine. Consistently, less lessreduced CTX-induced accumulation of intratumoral LAMP1/CD107a-expressing CD4 + T cells was less observed in mice receiving splenocytes derived from CCR5-deficient mouse-derived splenocytesmice than in those receiving splenocytes derived from WT mouse-derived splenocytesmice. Thus, CTX induces the expression of CCL3 to, which induces the intratumoral migration of CD4 + T cells with expressing cytotoxic molecules to induce , leading to tumor eradication and subsequent specific tumor immunity.