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closeReferee comments: Referee 2
Posted by PLOS_ONE_Group on 24 Apr 2008 at 13:33 GMT
Referee 2's review:
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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.
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The authors have investigated the impact of Treg depletion on anti-tumor immune therapy in a mouse GBM model.
Anti tumor response was found to be dependant on the size of the tumor at the time of Treg depletion, and while small sized tumors responded well to this treatment, no significant anti-tumor response was observed in larger tumors. These results suggested that tumor burden may be an additional factor in determining efficacy. Interestingly when Treg depletion was combined with intratumoral delivery of AdFlt3L and HSV-1TK with GCV it inhibited T cell dependant tumor regression. The authors further show results indicating that depletion of Treg in this model completely inhibited clonal expansion of tumor antigen specific T lymphocytes in response to the treatment. The manuscript is very logically organized and thorough.
The antitumor response observed in mice treated with PC61 15 days after tumor cell implantation did not correlate with any anti tumor T cell function as tested by the absence of DTH in mice. The authors should elaborate on the reason for this anti-tumor response in these mice.
In the section describing the results of Figure 3, the sentence "Depletion of Tregs 15 days after tumor regression significantly..."
Should this sentence read as?.. "Depletion of Tregs 15 days after tumor cell implantation significantly..."
RE: Referee comments: Referee 2
mg91991 replied to PLOS_ONE_Group on 29 Apr 2008 at 23:03 GMT
Below are the detailed responses to Referee 2 submitted to Journal during the resubmission of our manuscript:
1. “The antitumor response observed in mice treated with PC61 15 days after tumor cell implantation did not correlate with any anti tumor T cell function as tested by the absence of DTH in mice. The authors should elaborate on the reason for this anti-tumor response in these mice.”
Please see our response to Question 7 raised by Reviewer #1: “Treg depletion induced brain tumor regression and increased the survival of tumor bearing mice; only if depletion was done when the tumors were very small, i.e., 0.45mm3. These findings are in agreement with other reports that show an anti-tumor effect of T reg depletion in mouse models of neuroblastoma (see reference 40), leukemia, fibrosarcoma and myeloma (see reference 34). We observed that the antitumor effects of Treg depletion were not mediated by a T cell dependent anti-tumor immune response. Our results show that Treg depletion did not generate tumor-specific T cells as assed by ELISPOT assay (Fig. 6 D), nor did it induce anti-tumor immunological memory. These data suggest that the innate immune system could play a role in the anti-tumor effect elicited by Treg depletion in this model. In fact, T regs have been shown to inhibit the activity of the innate immune system by directly suppressing the cytotoxic effect of NK cells (see reference 41). This inhibitory mechanism is dependent on TGF-β and cell-cell contacts (see references 41-44). Since we found that NK cells comprise ~20% of the immune cells that infiltrate GL26 intracranial tumor (Fig. 1 C), the cytotoxic activity of these cells could be involved in the antitumor effects observed after T reg depletion (pages 14-15).”
2. “In the section describing the results of Figure 3, the sentence "Depletion of Tregs 15 days after tumor regression significantly..." Should this sentence read as: "Depletion of Tregs 15 days after tumor cell implantation significantly...?”
We thank Reviewer #2 for their careful examination of our manuscript and apologize for this error. We agree with this suggestion and have corrected the manuscript that now reads: "Depletion of Tregs 15 days after tumor cell implantation significantly” (see Page 10).